Phthalanilate compounds and methods of use

ABSTRACT

The invention provides antimicrobial compounds and compositions, and methods of using them. The compounds and compositions include, for example, a compound of any one of Formulas I-X. The invention further provides methods of preparing the compounds, and useful intermediates for their preparation. The compounds can possess highly specific and selective activity, such as antibacterial activity and/or enzymatic inhibitory activity. Accordingly, the compounds and compositions can be used to treat bacterial infections, or to inhibit or kill bacteria, either in vitro or in vivo.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/393,436, filed Feb. 29, 2012, issued as U.S. Pat. No. 8,859,620,which is a National Stage filing under 35 U.S.C. §371 ofPCT/US2010/047322, filed Aug. 31, 2010, which application claimspriority under 35 U.S.C. §119(e) to U.S. Provisional Patent ApplicationNo. 61/238,549, filed Aug. 31, 2009, which applications are incorporatedherein by reference.

GOVERNMENT INTEREST STATEMENT

This invention was made with government support under Grant No. GM061629awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF INVENTION

Penicillin-binding proteins (PBPs) are a group of enzymes involved inassembly of the cell wall in both gram negative and gram positivebacteria. They are characterized by their affinity for and binding ofpenicillin. There are a large number of PBPs, usually several in eachorganism, and are found as both membrane bound and cytoplasmic proteins.

Staphylococcus aureus (SA), a gram positive bacterium, has been linkedto several pathologies. Treatment and management of this disease andother bacterial infections is increasingly difficult due, at least inpart, to the emergence of antibiotic-resistant bacterial strains, forexample, methicillin-resistant Staphylococcus aureus (MRSA) andvancomycin-resistant methicillin-resistant Staphylococcus aureus.

S. aureus normally produces four penicillin-binding proteins (PBPs),which are know to be susceptible to modifications by β-lactamantibiotics, which can lead to bacterial death. The product of the genemecA from MRSA is another penicillin-binding protein (PBP), designatedPBP2a. Unfortunately, PBP2a has been found to be resistant to the actionof the vast majority of commercially available fl-lactam antibiotics.Furthermore, PBP2a is capable of taking over the functions of the otherPBPs of S. aureus in the face of the challenge by β-lactam antibiotics.

Accordingly, new compounds and compositions are needed that are capableof inhibiting bacteria, such as antibiotic-resistant bacterial strains.New compounds and compositions that can be used to treat bacterialinfections are also needed. Additionally, a model for screening andidentifying anti-bacterial agents against evolving new bacterial strainswould aid researchers in treating infectious diseases, such as thosecaused by antibiotic resistant strains of bacteria.

SUMMARY OF INVENTION

The invention provides compounds and compositions capable of inhibitingor killing bacteria, such as antibiotic-resistant bacteria, includingvancomycin-resistant bacteria, and/or treating a bacterial infection.Methods for screening and identifying active compounds are alsoprovided. Thus, the invention provides compositions that include anactive ingredient, which can be an antibiotic or combination ofantibiotic agents, effective to inhibit a microorganism such as abacterium and/or an antibiotic-resistant organism, such as MRSA. Theactive agents can also be effective for treating or inhibitingpenicillin-binding proteins (PBPs). The active agents can be one or morecompounds of Formulas I-X.

Accordingly, the invention provides a compound of Formula I:

wherein each Z is independently C, CH, N, or N-oxide;

R¹ is -L-R wherein L is —CO₂— or a direct bond, and R is H,1-imidazolyl, —(C₁-C₄)alkenyl, or —(C₁-C₈)alkyl-N((C₁-C₄)alkyl)₂;

R² is H, halo, or nitro;

R³ is H, halo, or nitro;

R⁴ is H, halo, nitro, —X-aryl, or absent;

R⁵ is H, halo, nitro, —X-aryl, or absent;

R⁶ is H, halo, nitro, —X-aryl, or absent;

R⁷ is H, halo, nitro, —X-aryl, or absent;

R⁸ is H, halo, or —X-aryl;

R⁹ is H, aryl, —(OCH₂CH₂)_(n)—(C₁-C₆)alkyl wherein n is 1-10, —Y-aryl,—Y—CH₂-aryl, —Y—(C₁-C₁₀)alkyl,

each X is independently 0, NH, or a direct bond;

each Y is independently 0, NH, S, SO₂, CH₂, carbonyl, or a direct bond;

wherein R⁴, R⁵, R⁶, or R⁷ is absent when the Z to which it is attachedis CH, N, or N-oxide; and

wherein any alkyl or aryl is optionally substituted with one or morealkyl, alkoxy, aryl, hydroxy, halo, amino, nitro, cyano,alkylsufonamide, —NH—CO₂-aryl, trifluoromethyl, or trifluoromethoxygroups, or a combination thereof;

or a pharmaceutically acceptable salt, solvate, prodrug, or a metabolitethereof. As would be recognized by one of skill in the art, severalcompounds of formula II-X are also compounds of Formula I. Additionally,several specific examples of compounds of Formula I are illustrated inFIGS. 1-17, as well as specific examples of compounds of Formulas II-X.

The invention also provides a compound of the Formula II:

wherein

W is hydrogen or oxygen;

X is absent or (C₁-C₂₄)alkylene;

Y is oxygen or sulfur;

Z is carbon or nitrogen, provided that when Z is nitrogen, R₈ is absent;

R₁ is carboxylic acid, (C₁-C₁₀)alkyl ester, —NR′2 where each R′ isindependently H or (C₁-C₁₀)alkyl;

R₂ is hydrogen or halogen;

R₃ is hydrogen, halogen, or —CONH(C₆-C₃₀)aryl;

R₄ and R₅ are each independently hydrogen, halogen, or nitro;

R₆, R₇, and R₁₁ are each independently hydrogen;

R₈ and R₉ are each independently absent or hydrogen;

R₁₀ is hydrogen, halogen, or —O(C₆-C₃₀)aryl; any (C₁-C₂₄)alkylene or(C₆-C₃₀)aryl can be optionally substituted on carbon with one or moreoxy, hydroxyl, halogen, (C₆-C₃₀)aryl, nitro, cyano, (C₁-C₆)alkoxy, ortrifluoromethyl groups or any combination thereof, and optionallysubstituted on carbon with one or more oxo, imino, or thio groups;

a is 0, 1, or 2; and

n is 0 or 1;

or a pharmaceutically acceptable salt, a prodrug, or a metabolitethereof

In one embodiment, W is hydrogen or oxygen; X is absent, —CH₂—, or—CH(CH₃)—; Y is oxygen or sulfur; Z is carbon or nitrogen; R₁ is —CO₂H;R₂ is hydrogen, fluorine, chlorine, or bromine; R₃ is hydrogen,fluorine, chlorine, bromine, or —CONH-(2-methoxy-4-nitro)phenyl; R₄ andR₅ are each independently hydrogen, fluorine, chlorine, bromine, ornitro; R₆, R₇, and R₁₁ are each independently hydrogen; R₈ and R₉ areeach independently absent or hydrogen; R₁₀ is hydrogen, chlorine, or—O-phenyl; a is 0, 1, or 2; and n is 0 or 1.

In certain embodiments, the compound of Formula II can include, forexample, compound 222, 239, 251, 253, 268, 277-3, 278-2, 296, 364, 365,381, 382, 385, 386, 387, 388, 389, 390, 393, 412, 414, 413, 414, 417,418, 419, 420, or 422, which are illustrated in Table 10.

The invention also provides a compound of the Formula III:

wherein

W is absent, oxygen, (C₁-C₂₄)alkylene, or carbonyl;

Y is oxygen or sulfur;

Z is carbon or nitrogen, provided that when Z is nitrogen, R₈ is absentor oxygen;

R₁ is carboxylic acid, thiocarboxylic acid, or a salt thereof;

R₂ is hydrogen, halogen, or nitro;

R₃ and R₄ are each independently hydrogen, halogen, or (C₁-C₂₄)alkyl;

R₅ is hydrogen or halogen;

R₆ is hydrogen or (C₁-C₂₄)alkyl;

R₇ is hydrogen or halogen;

R₈ is absent, hydrogen, or oxygen;

R₉ is hydrogen, halogen, (C₁-C₂₄)alkyl, —O(C₁-C₂₄)alkyl, or(C₁-C₂₄)alkylene(C₁-C₂₄)cycloalkyl;

R₁₀ is hydrogen, cyano, halogen, halo(C₁-C₂₄)alkyl,(C₁-C₂₄)alkylhydroxyl, or (C₁-C₂₄)alkyl;

R₁₀, R₁₁, and the atoms in between form a fused (C₆-C₃₀)aryl;

any (C₁-C₂₄)alkyl, (C₁-C₂₄)alkylene, (C₆-C₃₀)aryl, or (C₁-C₂₄)cycloalkylcan be optionally substituted on carbon with one or more oxy, hydroxyl,halogen, (C₆-C₃₀)aryl, nitro, cyano, (C₁-C₆)alkoxy, or trifluoromethylgroups or any combination thereof, and optionally exchanged on carbonwith one or more oxo, imino, or thio groups;

-   -   R₁₁ is hydrogen;        or a pharmaceutically acceptable salt, a prodrug, or a        metabolite thereof

In one embodiment, W is absent, oxygen, —CH₂—, or carbonyl; Y is oxygenor sulfur; Z is carbon or nitrogen; R₁ is —CO₂H, —CS₂H, —CO₂Na, or—COSH; R₂ is hydrogen, fluorine, chlorine, bromine, or nitro; R₃ and R₄are each independently hydrogen, fluorine, chlorine, bromine, or methyl;R₅ is hydrogen, fluorine, chlorine, or bromine; R₆ is hydrogen ormethyl; R₇ is hydrogen or chlorine; R₈ is absent, hydrogen, or oxygen;R₉ is hydrogen, chlorine, —(CH₂)₇CH₃, —(CH₂)₉CH₃, —(CH₂)₁₅CH₃,—O(CH₂)₃CH₃, —CH₂CH(OH)CH₂OCH₂(Cyclopropyl); or —CH₂CH(OH)CH₂O(CH₂)₃CH₃;R₁₀ is hydrogen, cyano, chlorine, trifluoromethyl, —CH₂OH, or methyl;R₁₀, R₁₁, and the atoms in between form a fused 3-hydroxyphenyl; and R₁₁is hydrogen.

In certain embodiments, the compound of Formula III can include, forexample, compound 44, 46, 85, 86, 89, 92, 93, 196, 201, 223, 232, 252,254, 256, 257, 262, 265, 270, 271, 274, 279-2, 280-2, 281-2, 288, 289,290, 291, 300, 301, 302, 303, 305, 307, 316, 318, 319, 329, 333, 334,343, 344, 345, 346, 355, 358, 360, which are illustrated in Table 10.

The invention also provides a compound of Formula IV:

wherein

W is oxygen or sulfur;

X is sulfur;

Y is oxygen;

Z is absent or (C₁-C₂₄)alkylene;

R₁, R₂, R₃, and R₄ are each independently halogen;

R₅, R₆, and R₉ are each independently hydrogen;

R₇ is (C₁-C₂₄)alkyl or (C₆-C₃₀)aryl;

any (C₁-C₂₄)alkyl, (C₁-C₂₄)alkylene, or (C₆-C₃₀)aryl can be optionallysubstituted on carbon with one or more oxy, hydroxyl, halogen,(C₆-C₃₀)aryl, nitro, cyano, (C₁-C₆)alkoxy, or trifluoromethyl groups orany combination thereof, and optionally exchanged on carbon with one ormore oxo, imino, or thio groups;

R₈ is hydrogen or halogen;

or a pharmaceutically acceptable salt, a prodrug, or a metabolitethereof

In one embodiment, W is oxygen or sulfur; X is sulfur; Y is oxygen; Z isabsent or —CH₂—; R₁, R₂, R₃, and R₄ are each independently chlorine orbromine; R₅, R₆, and R₉ are each independently hydrogen; R₇ is -phenylor —(CH₂)₇CH₃; and R₈ is hydrogen or chlorine.

In certain embodiments, the compound of Formula IV can include, forexample, compound 277-2, 280-1, 281-1, or 380-1, which are illustratedin Table 10.

The invention provides a compound of Formula V:

wherein

X is oxygen or sulfur;

R₁ is carboxylic acid;

R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₀, and R₁₁ are each independentlyhydrogen;

R₉ is (C₁-C₂₄)alkoxycarbonyl; or a pharmaceutically acceptable salt, aprodrug, or a metabolite thereof

In one embodiment, X is oxygen or sulfur; R₁ is —CO₂H; R₂, R₃, R₄, R₅,R₆, R₇, R₈, R₁₀, and R₁₁ are each independently hydrogen; and R₉ is—COO(CH₂)₃CH₃.

In certain embodiments, the compound of Formula V can include, forexample, compound 323 or 324, which are illustrated in Table 10.

The invention also provides a compound of Formula VI:

wherein

X is nitrogen, methoxy, amino, or hydroxyl;

R₁ is carboxylic acid or a salt thereof, or R₁ and R₂ and the atom inbetween form carbonyl;

R₂ is absent, hydrogen, or (C₁-C₂₄)alkyl, or (C₁-C₂₄)alkylenehydroxyl;

R₃ is absent, (C₁-C₂₄)alkyl, (C₁-C₂₄)alkylene,(C₁-C₂₄)alkylene(C₆-C₃₀)aryl, (C₃-C₃₀)heterocyclyl, or (C₆-C₃₀)aryl; any(C₁-C₂₄)alkyl, (C₁-C₂₄)alkylene, (C₃-C₃₀)heterocyclyl or (C₆-C₃₀)arylcan be optionally substituted on carbon with one or more oxy, hydroxyl,halogen, (C₆-C₃₀)aryl, nitro, cyano, oxo, (C₁-C₂₄)alkoxycarbonyl,(C₁-C₂₄)alkoxycarbonyl, —CO₂H, SO₃Na, CO₂Na, (C₁-C₆)alkoxy, ortrifluoromethyl groups or any combination thereof, and optionallyexchanged on carbon with one or more oxo, imino, or thio groups; or apharmaceutically acceptable salt, a prodrug, or a metabolite thereof

In one embodiment, X is nitrogen, methoxy, amino, or hydroxyl; R₁ is—CO₂H, —CO₂Na, or R₁ and R₂ and the atom in between form carbonyl; R₂ isabsent, hydrogen, methyl, or —(CH₂)₂OH; and R₃ is absent,—C(CH₂OH)CH₂CH₃, —C(CH₂OH)CHOH-phenyl, —CH₂CHOHCH₃, —C(CH₂OH)CHOHCH₃,—(3-chloro-4-(3-trifluoromethylphenyl)benzyl, —CH(CH₃)CHOH-phenyl,—CH(CH₃)-phenyl, —C(CH₂OH)CHOH-(4-nitrophenyl), —(CH₂)₃SO₃Na,—C(CO₂H)CH₂-(4-nitrophenyl),3-(acetoxymethyl)-7-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, or —C(CO₂Na)CH₂-(4-nitrophenyl).

In certain embodiments, the compound of Formula VI can include, forexample, compound 119, 120, 121, 122, 126, 127, 128, 129, 133, 134, 135,136, 138, 139, 140, 141, 142, 143, 144, 145, 146, or 427, which areillustrated in Table 10.

The invention also provides a compound of Formula VII:

wherein

X is absent or (C₁-C₂)alkylene;

----- is an optional bond;

R₁ is absent, hydrogen;

R₂ is hydrogen, (C₆-C₁₄)arylcarbonyloxy; or

R₁ and R₂ and the atom in between form a (C₁-C₂₄)cycloalkyl;

R₃ is hydrogen or phenyl, or

R₂, R₃, and the atoms in between form a (C₁-C₂₄)cycloalkyl, or phenyl,or (C₆-C₁₄)aryloxycarbonyl;

R₄ is absent or hydrogen;

R₅ is (C₁-C₈)alkyl;

R₆ is hydrogen;

R₇ is hydroxy(C₁-C₈)alkyl; or

R₅, R₆, R₇, and the atom in between form a (C₆-C₁₄)aryl or(C₃-C₁₄)heterocyclyl(C₆-C₁₄)aryl; and

any alkylene, alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl isoptionally substituted on carbon with one or more oxy, hydroxyl, halo,(C₆-C₁₄)aryl, (C₆-C₁₄)aryl(C₁-C₈)alkoxy, nitro, cyano, (C₁-C₆)alkoxy, ortrifluoromethyl groups or any combination thereof, and optionallyexchanged on carbon with one or more oxo, imino, or thio groups;

or a pharmaceutically acceptable salt, a prodrug, or a metabolitethereof

In one embodiment, X is absent or —CH₂—; R₁ is absent, hydrogen, or R₁and R₂ and the atom in between form a cyclopentyl; R₂ is hydrogen,—OCO-phenyl, or R₂, R₃, and the atoms in between form a3-methylcyclohexyl, 4-methylcyclohexyl, a cyclohexyl, 1-cyclopentyl, orR₃ is hydrogen, phenyl, or —OCO-phenyl; R₄ is absent or hydrogen; R₅ is—CH₂CH₃ or R₅, R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl, -4-(N-morpholino)phenyl, or-3-chloro-4-(O-benzyl)phenyl; R₆ is hydrogen; and R₇ is —CH₂OH.

In certain embodiments, the compound of Formula VII can include, forexample, compound 94, 95, 96, 97, 100, 158, 243, 246, or 253, which areillustrated in Table 10.

The invention provides a compound of Formula VIII:

wherein

R₁, R₂, R₃, and R₄ are each independently halogen;

R₅ is hydroxyl or (C₁-C₂₄)alkyl;

R₆ is hydrogen or (C₆-C₃₀)aryl;

any (C₁-C₂₄)alkyl or (C₆-C₃₀)aryl can be optionally substituted oncarbon with one or more oxy, hydroxyl, halogen, (C₆-C₃₀)aryl, nitro,cyano, (C₁-C₆)alkoxy, or trifluoromethyl groups or any combinationthereof, and optionally exchanged on carbon with one or more oxo, imino,or thio groups;

or a pharmaceutically acceptable salt, a prodrug, or a metabolitethereof

In one embodiment, R₁, R₂, R₃, and R₄ are each independently chlorine orbromine; R₅ is hydroxyl or methyl, and R₆ is hydrogen or 4-nitrophenyl.

In certain embodiments, the compound of Formula VIII can include, forexample, compound 217, 238, or 267, which are illustrated in Table 10.

The invention provides a compound of Formula IX:

wherein

R₁ and R₂ are each independently (C₆-C₁₄)arylcarbonyloxy or(C₁-C₂₄)alkylcarbonyloxy; or R₁ and R₂ together form a benzene ring,optionally substituted with one or two carboxy groups; and

any (C₁-C₂₄)alkoxycarbonyl or (C₆-C₃₀)aryl is optionally substituted oncarbon with one or more oxo, hydroxyl, halogen, (C₆-C₃₀)aryl, nitro,cyano, (C₁-C₆)alkoxy, or trifluoromethyl groups or any combinationthereof, and optionally exchanged on carbon with one or more oxo, imino,or thio groups; or a pharmaceutically acceptable salt, a prodrug, or ametabolite thereof.

In one embodiment, R₁ and R₂ are each independently —OBz or —OAc. Inanother embodiment, the compound of Formula IX is compound 108, 109,110, or 111, which are illustrated in Table 10.

The invention provides a compound of Formula X:

wherein

each R₁ is independently H, F, Cl, Br, or I, and n is 1, 2, 3, or 4;

Q is N or CH;

R₂ and R₃ are independently —NH₂, —N(alkyl)₂, N-imidazolyl, or—O-phenyl;

R₄ is H or —O—(CH₂)_(m)—R₅ wherein m is 1, 2, 3, or 4;

R₅ is —NH₂, —NH(alkyl), —N(alkyl)₂, or —N⁺(alkyl)(benzyl)X⁻ wherein X isa pharmaceutically acceptable anion;

any alkyl or phenyl of R₂ and any alkyl or benzyl of R₅ is optionallysubstituted on carbon with one or more oxo, hydroxyl, halogen,(C₁-C₈)alkyl, (C₆-C₁₄)aryl, nitro, cyano, (C₁-C₈)alkoxy,trifluoromethyl, or trifluoromethoxy groups or any combination thereof,and optionally exchanged on carbon with one or more oxo, imino, or thiogroups;

or a pharmaceutically acceptable salt, a prodrug, or a metabolitethereof

In one embodiment, the compound of Formula X is a compound illustratedin FIG. 18 or FIG. 19.

The invention yet further provides a pharmaceutical compositioncomprising one or more compounds of Formulas I-X; and a pharmaceuticallyacceptable diluent, excipient, or carrier. Examples of the compounds ofFormulas II-X are illustrated in Table 10 below. Specific suitableexamples include, but are not limited to, compound 271, 277-2, 277-3,278-2, 279-2, 280-1, 280-2, 281-2, 290, 300, 301, 382, 385, 386, 390,413, 414, 419, 420, and 422.

In other embodiments, the invention provides a method of treating ananimal inflicted with a bacterial infection by administering to ananimal in need of such treatment an effective amount of a compound ofany one of Formulas I-X. In various embodiments, the compound can be inthe form of a composition, as described herein.

The invention also provides a method of killing or inhibiting a bacteriacomprising contacting the bacteria with an effective amount of acompound of any one of Formulas I-X. In one embodiment, the contactingis in vitro. In one embodiment, the contacting is in vivo. The bacteriacan be a gram positive bacteria or a gram negative bacteria. Examples ofthe bacteria include, but are not limited to, S. aureus, Enterococcusfaecalis, Pseudomonas aeruginosa, Klebsiella pneumonia and Proteusmirabilis, as well as vancomycin-resistant methicillin-resistantStaphylococcus aureus.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the specification and are includedto further demonstrate certain embodiments or various aspects of theinvention. In some instances, embodiments of the invention can be bestunderstood by referring to the accompanying drawings in combination withthe detailed description presented herein. The description andaccompanying drawings may highlight a certain specific example, or acertain aspect of the invention, however, one skilled in the art willunderstand that portions of the example or aspect may be used incombination with other examples or aspects of the invention.

FIGS. 1-16 illustrate certain specific compounds of Formula I, accordingto various embodiments of the invention.

FIG. 17 illustrates certain compounds of Formula X, where n is 1, 2, 3,or 4, according to various embodiments.

FIG. 18 illustrates certain compounds of Formula X, where n is 1, 2, 3,or 4, and R is hydroxy, halo, (C₁-C₈)alkyl, (C₆-C₁₄)aryl, nitro, cyano,(C₁-C₈)alkoxy, trifluoromethyl, or trifluoromethoxy, according tovarious embodiments. The counterion may also be other halo anions, orother suitable pharmaceutically acceptable anions known in the art.

DETAILED DESCRIPTION OF THE INVENTION

One of ordinary skill in the art would readily appreciate that thepharmaceutical formulations and methods described herein can be preparedand practiced by applying known procedures in the pharmaceutical arts.These include, for example, unless otherwise indicated, conventionaltechniques of pharmaceutical sciences including pharmaceutical dosageform design, drug development, pharmacology, of organic chemistry, andpolymer sciences. See generally, for example, Remington: The Science andPractice of Pharmacy, 21^(st) edition, Lippincott, Williams & Wilkins(2005).

DEFINITIONS

Before the invention is described in such detail, however, it is to beunderstood that this invention is not limited to particular variationsset forth and may, of course, vary. Various changes may be made to theinvention described and equivalents may be substituted without departingfrom the true spirit and scope of the invention. In addition, manymodifications may be made to adapt a particular situation, material,composition of matter, process, process act(s) or step(s), to theobjective(s), spirit or scope of the invention. All such modificationsare intended to be within the scope of the claims made herein.

Methods recited herein may be carried out in any order of the recitedevents which is logically possible, as well as the recited order ofevents. Furthermore, where a range of values is provided, it isunderstood that every intervening value, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. Also, it iscontemplated that any optional feature of the inventive variationsdescribed may be set forth and claimed independently, or in combinationwith any one or more of the features described herein.

The referenced items are provided solely for their disclosure prior tothe filing date of the present application. Nothing herein is to beconstrued as an admission that the present invention is not entitled toantedate such material by virtue of prior invention.

References in the specification to “one embodiment”, “an embodiment”,“an example embodiment”, etc., indicate that the embodiment describedmay include a particular aspect, feature, structure, moiety, orcharacteristic, but not every embodiment necessarily includes thataspect, feature, structure, moiety, or characteristic. Moreover, suchphrases may, but do not necessarily, refer to the same embodimentreferred to in other portions of the specification. Further, when aparticular aspect, feature, structure, moiety, or characteristic isdescribed in connection with an embodiment, it is within the knowledgeof one skilled in the art to affect such aspect, feature, structure,moiety, or characteristic in connection with other embodiments, whetheror not explicitly described.

Reference to a compound of Formulas I-X refers to a compound of any oneof Formulas I, II, III, IV, V, VI, VII, VIII, IX, or X; or a combinationof any two or more of such formulas. In some embodiments, only a subsetof Formulas I-X may be included in the subject matter of interest.

Unless otherwise indicated, the words and phrases presented in thisdocument have their ordinary meanings to one of skill in the art. Suchordinary meanings can be obtained by reference to their use in the artand by reference to general and scientific dictionaries, for example,Webster's Third New International Dictionary, Merriam-Webster Inc.,Springfield, Mass., 1993, The American Heritage Dictionary of theEnglish Language, Houghton Mifflin, Boston Mass., 1981, and Hawley'sCondensed Chemical Dictionary, 14^(th) edition, Wiley Europe, 2002.

The following explanations of certain terms are meant to be illustrativerather than exhaustive. These terms have their ordinary meanings givenby usage in the art and in addition include the following explanations.

The term “about” can refer to a variation of ±5%, ±10%, ±20%, or ±25% ofthe value specified. For example, “about 50” percent can in someembodiments carry a variation from 45 to 55 percent. For integer ranges,the term “about” can include one or two integers greater than and/orless than a recited integer. Unless indicated otherwise herein, the term“about” is intended to include values, e.g., weight percents, proximateto the recited range that are equivalent in terms of the functionalityof the individual ingredient, the composition, or the embodiment. Inaddition, unless indicated otherwise herein, a recited range (e.g.,weight percents or carbon groups) includes each specific value, integer,decimal, or identity within the range.

As used herein, the term “and/or” refers to any one of the items, anycombination of the items, or all of the items with which this term isassociated.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only,” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

The term “acyl” group refers to a group containing a carbonyl moietywherein the group is bonded via the carbonyl carbon atom. The carbonylcarbon atom is also bonded to another carbon atom, which can be part ofan alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In thespecial case wherein the carbonyl carbon atom is bonded to a hydrogenatom, the group is a “formyl” group, an acyl group as the term isdefined herein. Other examples include acetyl, benzoyl, phenylacetyl,pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When thegroup containing the carbon atom that is bonded to the carbonyl carbonatom contains a halogen, the group is termed a “haloacyl” group. Anexample is a trifluoroacetyl group.

The term “adjuvant” refers to an agent that may affect any of (1) therate of release of the drug; (2) the stability of the drug; (3) thesolubility of the drug; or (4) physicochemical characteristics of thecore itself, including compactness, pH, etc. However, an adjuvant doesnot include those ingredients that affect the release rate by providingan osmotic pressure or ion gradient. In one aspect, adjuvants mayinclude solubilizing agents, solubility decreasing agents, anddispersing agents.

The term “amino” refers to —NH₂. The amino group can be optionallysubstituted as defined herein for the term “substituted.” The term“alkylamino” refers to —NR₂, wherein at least one R is alkyl and thesecond R is alkyl or hydrogen. The term “acylamino” refers toN(R)C(═O)R, wherein each R is independently hydrogen, alkyl, or aryl.

The terms “amide” (or “amido”) refer to C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to carbamoyl groups (—C(O)NH₂) and formamidegroups (—NHC(O)H).

The term “alkanoyl” or “alkylcarbonyl” refers to —C(═O)R, wherein R isan alkyl group as previously defined.

The term “acyloxy” or “alkylcarboxy” refers to —O—C(═O)R, wherein R isan alkyl group as previously defined. Examples of acyloxy groupsinclude, but are not limited to, acetoxy, propanoyloxy, butanoyloxy, andpentanoyloxy. Any alkyl group as defined above can be used to form anacyloxy group.

The term “alkoxycarbonyl” refers to —C(═O)OR (or “COOR”), wherein R isan alkyl group as previously defined.

The term “alkyl” refers to a C₁-C₁₈ hydrocarbon containing normal,secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (iso-butyl,—CH₂CH(CH₃)₂), 2-butyl (sec-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl(tert-butyl, —C(CH₃)₃), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl. The alkyl can be a monovalent hydrocarbon radical,as described and exemplified above, or it can be a divalent hydrocarbonradical (i.e., alkylene).

The alkyl can optionally be substituted with one or more alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl or hydroxy. The alkyl can optionallybe interrupted with one or more non-peroxide oxy (—O—), thio (—S—),imino (—N(H)—), methylene dioxy (—OCH₂O—), carbonyl (—C(═O)—), carboxy(—C(═O)O—), carbonyldioxy (—OC(═O)O—), carboxylato (—OC(═O)—), imino(C═NH), sulfinyl (SO) or sulfonyl (SO₂). Additionally, the alkyl canoptionally be at least partially unsaturated, thereby providing analkenyl.

The term “alkenyl” refers to a C₂-C₁₈ hydrocarbon containing normal,secondary, tertiary or cyclic carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond. Examples include,but are not limited to: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂),cyclopentenyl (—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂). The alkenylcan be a movalent hydrocarbon radical, as described and exemplifiedabove, or it can be a divalent hydrocarbon radical (i.e., alkenylene).

The alkenyl can optionally be substituted with one or more alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, thealkenyl can optionally be interrupted with one or more non-peroxide oxy(—O—), thio (—S—), imino (—N(H)—), methylene dioxy (—OCH₂O—), carbonyl(—C(═O)—), carboxy (—C(═O)O—), carbonyldioxy (—OC(═O)O—), carboxylato(—OC(═O)—), imine (C═NH), sulfinyl (SO) or sulfonyl (SO₂).

The term “alkylene” refers to a saturated, branched or straight chain orcyclic hydrocarbon radical of 1-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or different carbon atoms of a parent alkane. Typicalalkylene radicals include, but are not limited to: methylene (—CH₂—)1,2-ethylene (—CH₂CH₂—), 1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene(—CH₂CH₂CH₂CH₂—), and the like.

The alkylene can optionally be substituted with one or more alkoxy,halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, thealkylene can optionally be interrupted with one or more non-peroxide oxy(—O—), thio (—S—), imino (—N(H)—), methylene dioxy (—OCH₂O—), carbonyl(—C(═O)—), carboxy (—C(═O)O—), carbonyldioxy (—OC(═O)O—), carboxylato(—OC(═O)—), imine (C═NH), sulfinyl (SO) or sulfonyl (SO₂). Moreover, thealkylene can optionally be at least partially unsaturated, therebyproviding an alkenylene.

The term “alkenylene” refers to an unsaturated, branched or straightchain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to: 1,2-ethenylene(—CH═CH—).

The alkenylene can optionally be substituted with one or more alkoxy,halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, Thealkenylene can optionally be interrupted with one or more non-peroxideoxy (—O—), thio (—S—), imino (—N(H)—), methylene dioxy (—OCH₂O—),carbonyl (—C(═O)—), carboxy (—C(═O)O—), carbonyldioxy (—OC(═O)O—),carboxylato (—OC(═O)—), imine (C═NH), sulfinyl (SO) or sulfonyl (SO₂).

The term “alkoxy” refers to the group alkyl-O—, where alkyl is definedherein. Preferred alkoxy groups include, e.g., methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, 1,2-dimethylbutoxy, and the like.

The alkoxy can optionally be substituted with one or more halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl, or hydroxy.

The term “antimicrobial” refers to a molecular entity that is effectiveas a therapeutic agent or as a protective agent against an infection bya microorganism, which could be a bacterium, a protozoan, a fungus, avirus, or another pathogenic living organism. In many embodiments, thecompounds described herein have antimicrobial activity. An antimicrobialmay be an antibiotic, effective against bacteria, includingaminoglycoside antibiotics such as gentamicin or streptomycin, acephalosporin such as cephalexin or cephtriaxone, a carbacephem such asloracarbef, a glycopeptide such as vancomycin, a macrolide such aserythromycin, a penicillin such as amoxicillin or ampicillin, apolypeptide such as bacitracin or polymyxin B, a quinolone such asciprofloxacin, a tetracycline such as oxytetracycline, a sulfonamide, orany other medically approved agent for treatment of bacterialinfections. Alternatively the antimicrobial may be an antifungal agentsuch as ketoconazole, miconazole or amphotericin B, or an antiviralagent such as acyclovir or AZT.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings, wherein at least one ring is aromatic(e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferredaryls include phenyl, naphthyl and the like. The aryl can optionally bea divalent radical, thereby providing an arylene.

The aryl can optionally be substituted with one or more alkyl, alkenyl,alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino,alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

The term “binder” refers to a pharmacologically inert substance, whichis suitable for human consumption and serves to hold the constituents ofa tablet together after compression forming of the tablet has occurred.

The term “carbocycle” refers to a saturated, unsaturated or aromaticring having 3 to 8 carbon atoms as a monocycle, 7 to 12 carbon atoms asa bicycle, and up to about 30 carbon atoms as a polycycle. Monocycliccarbocycles typically have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo[5,6] or [6,6] system. Examples ofcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryland naphthyl. The carbocycle can be optionally substituted as describedabove for alkyl groups.

The term “carboxy” or “carboxyl” refers to —CO₂H.

All chiral, diastereomeric, racemic forms of a structure are intended,unless the specific stereochemistry or isomeric form is specificallyindicated. Compounds used in the invention include enriched or resolvedoptical isomers at any or all asymmetric atoms as are apparent from thedepictions. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers can be isolated or synthesized so as to besubstantially free of their enantiomeric or diastereomeric partners, andthese are all within the scope of the invention.

The term “chemically feasible” refers to a bonding arrangement or acompound where the generally understood rules of organic structure arenot violated; for example a structure within a definition of a claimthat would contain in certain situations a pentavalent carbon atom thatwould not exist in nature would be understood to not be within theclaim.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other by achemically feasible bonding configuration.

The phrase “compounds of the invention” refer to compounds of FormulasI-X, and pharmaceutically acceptable enantiomers, diastereomers, salts,or solvates thereof. Similarly, references to intermediates, are meantto embrace their salts or solvates where the context so permits.

The term “contacting” refers to the act of touching, making contact, orof bringing to immediate or close proximity, including at the molecularlevel, for example, to bring about a chemical reaction, physical change,or biological interaction, e.g., in a solution or other reactionmixture, or in a biological assay.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to about20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

The cycloalkyl can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, WRY and/or COM wherein each R^(x) and R^(y) are independentlyH, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, orhydroxy.

The cycloalkyl can optionally be at least partially unsaturated, therebyproviding a cycloalkenyl. Additionally, the cycloalkyl can optionally bea divalent radical, thereby providing a cycloalkylene.

The term “derivative” of a compound refers to a chemically modifiedcompound wherein the chemical modification takes place at one or morefunctional groups of the compound and/or on an aromatic, alicyclic, orheterocyclic structures, when present. The derivative however isexpected to retain the pharmacological activity of the compound fromwhich it is derived.

The term “diluent” refers to a pharmacologically inert substance that isnevertheless suitable for human consumption that serves as an excipientin the inventive dosage form. A diluent serves to dilute the API in theinventive dosage form, such that tablets of a typical size can beprepared incorporating a wide range of actual doses of the API.

The term “disintegrant” refers to substance that assists in dissolutionof the dosage form after oral ingestion. It is believed to assist inhydration and to avoid the formation of gels in the stomach of thepatient as the tablet dissolves, thus assisting in the release of theAPI into the gastric juices so that it can be absorbed into thebloodstream.

The term “dispersing agent” refers to an agent that facilitates theformation of a dispersion of one or more internal phases in a continuousphase. Examples of such dispersions include suspensions and emulsions,wherein the continuous phase may be water, for example, and the internalphase is a solid or a water-immiscible liquid, respectively. Thus,dispersing agents may include suspending agents and emulsifying agents.

The term “dosage form” refers to a physical and chemical composition ofan active pharmaceutical ingredient (API) that is adapted foradministration to a patient in need thereof. The inventive dosage formis a tablet. By a tablet is meant a relatively hard, compact object,suitable for oral ingestion, prepared by compression of a powderincluding an active pharmaceutical ingredient and, usually, excipients.

The term “drug” refers to a therapeutic agent or a diagnostic agent andincludes any substance, other than food, used in the prevention,diagnosis, alleviation, treatment, or cure of a disease. Stedman'sMedical Dictionary, 25^(th) Edition (1990). The drug can include anysubstance disclosed in at least one of: The Merck Index, 13^(th)Edition, 1998, published by Merck & Co., Rahway, N.J.; Pei-Show Juo,Concise Dictionary of Biomedicine and Molecular Biology, (1996); U.S.Pharmacopeia Dictionary, 2000 Edition; and Physician's Desk Reference,2001 Edition.

The term “an effective amount” refers to an amount sufficient to effectbeneficial or desired results. An effective amount can be administeredin one or more administrations, applications, or dosages. Determinationof an effective amount for a given administration is well within theordinary skill in the pharmaceutical arts.

The terms “ethylenically unsaturated group” or “olefinically unsaturatedgroup” are employed herein in a broad sense and is intended to encompassany groups containing at least one C═C group. Exemplary ethylenicallyunsaturated groups include without limitation acryloyl, methacryloyl,allyl, vinyl, styrenyl, or other C═C containing groups.

The term “excipient” refers to an ingredient of the dosage form that isnot medicinally active, but serves to dilute the API, assist indispersion of the tablet in the patient's stomach, bind the tablettogether, and serve other functions like stabilizing the API againstdecomposition.

The term “glidant” refers to a substance that assists in maintainingfavorable powder flow properties of the powder materials that arecompressed to form the inventive tablet.

The term “halo” refers to fluoro, chloro, bromo, and iodo. Similarly,the term “halogen” refers to fluorine, chlorine, bromine, and iodine.

The term “haloalkyl” refers to alkyl as defined herein substituted by1-4 halo groups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” is defined herein as a monocyclic, bicyclic, ortricyclic ring system containing one, two, or three aromatic rings andcontaining at least one nitrogen, oxygen, or sulfur atom in an aromaticring, and which can be unsubstituted or substituted. The heteroaryl canoptionally be a divalent radical, thereby providing a heteroarylene.

Examples of heteroaryl groups include, but are not limited to,2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl, acridinyl,benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl,cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl,imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl,naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl,triazolyl, and xanthenyl. In one embodiment the term “heteroaryl”denotes a monocyclic aromatic ring containing five or six ring atomscontaining carbon and 1, 2, 3, or 4 heteroatoms independently selectedfrom the group non-peroxide oxygen, sulfur, and N(Z) wherein Z is absentor is H, 0, alkyl, phenyl, or benzyl. In another embodiment heteroaryldenotes an ortho-fused bicyclic heterocycle of about eight to ten ringatoms derived therefrom, particularly a benz-derivative or one derivedby fusing a propylene, or tetramethylene diradical thereto.

The heteroaryl can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The term “heterocycle” or “heterocyclyl” refers to a saturated orpartially unsaturated ring system, containing at least one heteroatomselected from the group oxygen, nitrogen, and sulfur, and optionallysubstituted with alkyl, or C(═O)OR^(b), wherein R^(b) is hydrogen oralkyl. Typically heterocycle is a monocyclic, bicyclic, or tricyclicgroup containing one or more heteroatoms selected from the group oxygen,nitrogen, and sulfur. A heterocycle group also can contain an oxo group(═O) attached to the ring. Non-limiting examples of heterocycle groupsinclude 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane,2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl,imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine,piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl,pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine.The heterocycle can optionally be a divalent radical, thereby providinga heterocyclene.

The heterocycle can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each IV and R^(3′) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “include,” “for example,” “such as,” and the like are usedillustratively and are not intended to limit the present invention.

The terms “individual,” “host,” “subject,” and “patient” are usedinterchangeably, and refer to a mammal, including, but not limited to,primates, including simians and humans.

The term “inhibitor” refers to an agent that inhibits the growth ofmicrobes, such as bacteria. Examples of inhibitors include the compoundsdescribed herein.

The term “keto” refers to (C═O). The term “oxo” refers to ═O.

As to any of the groups described herein, which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this disclosed subject matter include all stereochemicalisomers arising from the substitution of these compounds.

Selected substituents within the compounds described herein are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. One of ordinary skill in the art ofmedicinal chemistry and organic chemistry understands that the totalnumber of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

Recursive substituents are an intended aspect of the disclosed subjectmatter. One of ordinary skill in the art of medicinal and organicchemistry understands the versatility of such substituents. To thedegree that recursive substituents are present in an claim of thedisclosed subject matter, the total number will be determined as setforth above.

The term “infection” refers to the invasion of the host by germs thatreproduce and multiply, causing disease by local cell injury, release ofpoisons, or germ-antibody reaction in the cells. The infection can be ina mammal (e.g., human).

The term “lubricant” refers to a substance that is useful in the tabletcompression process, serving to lubricate metal parts of the tablet die.

The term “mammal” refers to any of a class of warm-blooded highervertebrates that nourish their young with milk secreted by mammaryglands and have skin usually more or less covered with hair, andnon-exclusively includes humans and non-human primates, their children,including neonates and adolescents, both male and female, livestockspecies, such as horses, cattle, sheep, and goats, and research anddomestic species, including dogs, cats, mice, rats, guinea pigs, andrabbits.

The term “metabolite” refers to any compound of Formulas I-X produced invivo or in vitro from the parent drug(compound), or its prodrug.

The term “microbe” refers to an organism that is too small to be seen bythe naked human eye. As used herein, the term “microbe” refers to abacterium, a fungus, an archaea, or a protist.

The term “molecular weight” refers to a weight-average molecular weight,as is well known in the art.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or condition may but need not occur, and that thedescription includes instances where the event or condition occurs andinstances in which it does not. For example, “optionally substituted”means that the named substituent may be present but need not be presentin a specific embodiment, and the description includes situations wherethe named substituent is included and situations where the namedsubstituent is not included.

The term “patient” refers to a warm-blooded animal, and preferably amammal, for example, a cat, dog, horse, cow, pig, mouse, rat, orprimate, including a human.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problems or complications commensurate witha reasonable benefit/risk ratio. Several pharmaceutically acceptableingredients are known in the art and official publications such as TheUnited States Pharmacoepia describe the analytical criteria to assessthe pharmaceutical acceptability of numerous ingredients of interest.

The term “pharmaceutically acceptable salts” refers to ionic compounds,wherein a parent non-ionic compound is modified by making acid or basesalts thereof. Examples of pharmaceutically acceptable salts include,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include conventionalnon-toxic salts and quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids.Non-toxic salts can include those derived from inorganic acids such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric,nitric and the like. Salts prepared from organic acids can include thosesuch as acetic, 2-acetoxybenzoic, ascorbic, behenic, benzenesulfonic,benzoic, citric, ethanesulfonic, ethane disulfonic, formic, fumaric,gentisinic, glucaronic, gluconic, glutamic, glycolic, hydroxymaleic,isethionic, isonicotinic, lactic, maleic, malic, mesylate ormethanesulfonic, oxalic, pamoic(1,1′-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic,phenylacetic, propionic, salicylic, sulfanilic, toluenesulfonic,stearic, succinic, tartaric, bitartaric, and the like. Certain compoundscan form pharmaceutically acceptable salts with various amino acids. Fora review on pharmaceutically acceptable salts, see, e.g., Berge et al.,J. Pharm. Sci. 1977, 66(1), 1-19, which is incorporated herein byreference.

The pharmaceutically acceptable salts of the compounds described hereincan be synthesized from the parent compound, which contains a basic oracidic moiety, by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of many suitable saltsare found in Remington: The Science and Practice of Pharmacy, 21^(st)edition, Lippincott, Williams & Wilkins, (2005).

It will be appreciated by those skilled in the art that compounds usefulin the disclosed subject matter having a chiral center may exist in andbe isolated in optically active and racemic forms. Some compounds mayexhibit polymorphism. It is to be understood that the presentlydisclosed subject matter encompasses any racemic, optically-active,polymorphic, or stereoisomeric form, or mixtures thereof, of a compoundof the presently disclosed subject matter, which possess the usefulproperties described herein, it being well known in the art how toprepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase) and how todetermine anti-HCV activity using the standard tests described herein,or using other similar tests which are well known in the art.

One diastereomer of a compound disclosed herein may display superioractivity compared with the other. When required, separation of theracemic material can be achieved by HPLC using a chiral column or by aresolution using a resolving agent such as camphonic chloride as inTucker et al., J. Med. Chem., 37, 2437 (1994). A chiral compounddescribed herein may also be directly synthesized using a chiralcatalyst or a chiral ligand, e.g., Huffinan et al., J. Org. Chem.,60:1590 (1995).

The terms “preferred” and “preferably” refer to embodiments of theinvention that may afford certain benefits, under certain circumstances.However, other embodiments may also be preferred, under the same orother circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the invention.

The terms “prevent,” “preventative,” “prevention,” “protect,” and“protection” refer to medical procedures that keep the malcondition fromoccurring in the first place. The terms mean that there is no or alessened development of disease or disorder where none had previouslyoccurred, or no further disorder or disease development if there hadalready been development of the disorder or disease.

The term “prodrug” refers to any pharmaceutically acceptable form of acompound of Formulas I-X, which, upon administration to a patient,provides a compound of any one of Formulas I-X. Pharmaceuticallyacceptable prodrugs refer to a compound that is metabolized, for examplehydrolyzed or oxidized, in the host to form a compound of any one ofFormulas I-X. Typical examples of prodrugs include compounds that havebiologically labile protecting groups on a functional moiety of theactive compound. Prodrugs include compounds that can be oxidized,reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed,dehydrolyzed, alkylated, dealkylated, acylated, deacylated,phosphorylated, dephosphorylated to produce the active compound.

The prodrug can be readily prepared from the compounds of Formulas I-Xusing methods known in the art. See, e.g., See Notari, R. E., “Theoryand Practice of Prodrug Kinetics,” Methods in Enzymology, 112:309 323(1985); Bodor, N., “Novel Approaches in Prodrug Design,” Drugs of theFuture, 6(3):165 182 (1981); and Bundgaard, H., “Design of Prodrugs:Bioreversible-Derivatives for Various Functional Groups and ChemicalEntities,” in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y.(1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol.1, pp. 172 178, 949 982 (1995).

The prodrug may be prepared with the objective(s) of improved chemicalstability, improved patient acceptance and compliance, improvedbioavailability, prolonged duration of action, improved organselectivity (including improved brain penetrance), improved formulation(e.g., increased hydrosolubility), and/or decreased side effects (e.g.,toxicity). See e.g., T. Higuchi and V. Stella, “Prodrugs as NovelDelivery Systems”, Vol. 14 of the A.C.S. Symposium Series; BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, (1987). Prodrugs include, but are notlimited to, compounds derived from compounds of Formulas I-X, wherein ahydroxy, amine or sulfhydryl groups, if present, are bonded to any groupthat, when administered to the subject, cleaves to form the freehydroxyl, amino or sulfhydryl group, respectively. Selected examplesinclude, but are not limited to, biohydrolyzable amides andbiohydrolyzable esters and biohydrolyzable carbamates, carbonates,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups.

The term “protecting group” refers to any group which, when bound to ahydroxyl, nitrogen, or other heteroatom prevents undesired reactionsfrom occurring at this group and which can be removed by conventionalchemical or enzymatic steps to reestablish the original group. Theparticular removable protecting group employed is typically notcritical. Some removable protecting groups include conventionalsubstituents such as, for example, allyl, benzyl, acetyl, chloroacetyl,thiobenzyl, benzylidine, phenacyl, methyl methoxy, silyl ethers (e.g.,trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), ort-butyldimethylsilyl (TBS)) and any other group that can be introducedchemically onto a functionality and later selectively removed either bychemical or enzymatic methods in mild conditions compatible with thenature of the product.

A large number of protecting groups and corresponding chemical cleavagereactions are described in Protective Groups in Organic Synthesis,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN0-471-62301-6) (“Greene”, which is incorporated herein by reference inits entirety). Included therein are hydroxyl and nitrogen protectinggroups, for example, amide-forming groups. In particular, see Chapter 1,Protecting Groups: An Overview, pages 1-20, Chapter 2, HydroxylProtecting Groups, pages 21-94, Chapter 4, Carboxyl Protecting Groups,pages 118-154, and Chapter 5, Carbonyl Protecting Groups, pages 155-184.See also Kocienski, Philip J.; Protecting Groups (Georg Thieme VerlagStuttgart, New York, 1994), which is incorporated herein by reference inits entirety.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute (e.g., a compound of a formula described herein, or a saltor physiologically functional derivative thereof) and a solvent. Suchsolvents, for the purpose of the invention, should not interfere withthe biological activity of the solute. Non-limiting examples of suitablesolvents include, but are not limited to water, methanol, ethanol, andacetic acid. Preferably the solvent used is a pharmaceuticallyacceptable solvent.

The term “stereoisomer” refers to a compound made up of the same atomsbonded by the same bonds but having different three-dimensionalstructures, which are not interchangeable.

The term “solubility” refers to the extent to which a solute dissolvesin a solvent, wherein the solute and “solvent” may be of the same or ofdifferent physical state. Thus, a solution of a solid or a liquid in any“solvent” such as a solid, liquid or gas is within the scope of thisterm. Solubility can be expressed in many ways, such as: weight/volume(grams/mL); molality (number of moles of solute/1000 grams of solvent);mol fraction (fraction of the total number of moles present which aremole of one component); mol % (mol fraction.times.100); normality(number of gram equivalent weights of solute dissolved in 1000 mL ofsolution); % by weight (% w/w); % weight in volume (% w/v); % by volume(% v/v). Solubility can also be described by terms such as: very soluble(less than 1 part of solvent per 1 part of solute); freely soluble (from1 to 10 parts of solvent per 1 part of solute); soluble (from 10 to 30parts of solvent per 1 part of solute); sparingly soluble (from 30 to100 parts of solvent for 1 part of solute); slightly soluble (from 100to 1000 parts of solvent for 1 part of solute); very slightly soluble(from 1000 to 10,000 parts of solvent for 1 part of solute); andpractically insoluble, or insoluble (more than 10,000 parts of solventfor 1 part of solute). For further elaboration, see Remington, supra,Chapter 16, which is incorporated by reference.

The terms “stable compound” and “stable structure” are meant to indicatea compound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. Only stable compounds are contemplatedherein.

The term “substituted” is intended to indicate that one or more (e.g.,1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in otherembodiments 1 or 2) hydrogens on the group indicated in the expressionusing “substituted” is replaced with one or more of a selection from theindicated group(s) or with a suitable group known to those of skill inthe art, provided that the indicated atom's normal valency is notexceeded, and that the substitution results in a stable compound. Aswould be readily understood by one skilled in the art, when asubstituent is keto (═O) or thioxo (═S), or the like, then two hydrogenatoms on the substituted atom are replaced. One or more substituentsrecited above can be excluded from a formula or specific embodiment.

The term “therapeutic agent” refers any agent which serves to repairdamage to a living organism to heal the organism, to cure amalcondition, to combat an infection by a microorganism or a virus, toassist the body of the living mammal to return to a healthy state.

The term “therapeutic composition” refers to an admixture with anorganic or inorganic carrier or excipient, and can be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, or other form suitable for use.

The term “therapeutically effective amount” is intended to include anamount of a compound described herein, or an amount of the combinationof compounds described herein, e.g., to treat or prevent the disease ordisorder, or to treat the symptoms of the disease or disorder, in ahost. The combination of compounds is preferably a synergisticcombination. Synergy, as described for example by Chou and Talalay, Adv.Enzyme Regul., 22:27 (1984), occurs when the effect of the compoundswhen administered in combination is greater than the additive effect ofthe compounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased activity, or some other beneficial effect of thecombination compared with the individual components.

The terms “therapy,” and “therapeutic” refer to either “treatment” or“prevention,” thus, agents that either treat damage or prevent damageare “therapeutic.”

The terms “treating”, “treat” and “treatment” include (i) preventing adisease, pathologic or medical condition from occurring (e.g.,prophylaxis); (ii) inhibiting the disease, pathologic or medicalcondition or arresting its development; (iii) relieving the disease,pathologic or medical condition; and/or (iv) diminishing symptomsassociated with the disease, pathologic or medical condition. Thus, theterms “treat”, “treatment”, and “treating” extend to prophylaxis andinclude prevent, prevention, preventing, lowering, stopping or reversingthe progression or severity of the condition or symptoms being treated.As such, the term “treatment” includes both medical, therapeutic, and/orprophylactic administration, as appropriate.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the embodiments recited herein.

Asymmetric carbon atoms may be present in the compounds described. Allsuch isomers, including diastereomers and enantiomers, as well as themixtures thereof, are intended to be included in the scope of therecited compound. In certain cases, compounds can exist in tautomericforms. All tautomeric forms are intended to be included in the scope.Likewise, when compounds contain an alkenyl or alkenylene group, thereexists the possibility of cis- and trans-isomeric forms of thecompounds. Both cis- and trans-isomers, as well as the mixtures of cis-and trans-isomers, are contemplated. Thus, reference herein to acompound includes all of the aforementioned isomeric forms unless thecontext clearly dictates otherwise.

Various forms are included in the embodiments, including polymorphs,solvates, hydrates, conformers, salts, and prodrug derivatives. Apolymorph is a composition having the same chemical formula, but adifferent structure. A solvate is a composition formed by solvation (thecombination of solvent molecules with molecules or ions of the solute).A hydrate is a compound formed by an incorporation of water. A conformeris a structure that is a conformational isomer. Conformational isomerismis the phenomenon of molecules with the same structural formula butdifferent conformations (conformers) of atoms about a rotating bond.Salts of compounds can be prepared by methods known to those skilled inthe art. For example, salts can be prepared by reacting the appropriatebase or acid with a stoichiometric equivalent of a compound. A prodrugis a compound that undergoes biotransformation (chemical conversion)before exhibiting its pharmacological effects. For example, a prodrugcan thus be viewed as a drug containing specialized protective groupsused in a transient manner to alter or to eliminate undesirableproperties in the parent molecule. Thus, reference herein to a compoundincludes all of the aforementioned forms unless the context clearlydictates otherwise.

Concentrations, amounts, etc., of various components are often presentedin a range format throughout this disclosure. The description in rangeformat is merely for convenience and brevity and should not be construedas an inflexible limitation on the scope of the claimed invention.Accordingly, the description of a range should be considered to havespecifically disclosed all the possible subranges as well as individualnumerical values within that range. For example, description of a rangesuch as 1% to 8% should be considered to have specifically disclosedsubranges such as 1% to 7%, 2% to 8%, 2% to 6%, 3% to 6%, 4% to 8%, 3%to 8% etc., as well as individual numbers within that range, such as,2%, 5%, 7% etc. This construction applies regardless of the breadth ofthe range and in all contexts throughout this disclosure.

Compounds of the Invention:

Compounds of the invention include compounds of the Formulas describedherein, which can be used for treating, inhibiting, or killing bacteria,or for treatment of associated conditions. These compounds are furtherdefined in Tables 1-9 below.

Table 1. Compounds of Formula II.

Compound 382 includes: W is oxygen; X is —CH(CH3)-; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is hydrogen; R3 is bromine; R10 is chlorine; R4 isbromine; R11 is hydrogen; R5 is bromine; a is 1, n is 1.

Compound 385 includes: W is oxygen; X is —CH2-; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO₂H; R8 is hydrogen; R2is chlorine; R9 is 2-methyl; R3 is chlorine; R10 is chlorine; R4 ischlorine; R11 is hydrogen; R5 is chlorine; a is 1, n is 1.

Compound 386 includes: W is oxygen; X is —CH2-; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is 2-methyl; R3 is bromine; R10 is chlorine; R₄ isbromine; R₁₁ is hydrogen; R₅ is bromine; a is 1, n is 1.

Compound 390 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R₂ is bromine; R₁₀ is chlorine; R3 isbromine; R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 413 includes: W is oxygen; R5 is chlorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is chlorine; R10 ishydrogen; R3 is chlorine; R11 is hydrogen; R4 is chlorine; a is 2, n is1.

Compound 414 includes: W is oxygen; R5 is bromine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is bromine; R10 is hydrogen;R3 is bromine; R11 is hydrogen; R4 is bromine; a is 2, n is 1.

Compound 418 includes: W is oxygen; R5 is fluorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is fluorine; R10 is chlorine;R3 is fluorine; R11 is hydrogen; R4 is fluorine; a is 1, n is 1.Compound 419 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is chlorine; R10 is chlorine;R3 is chlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 420 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is bromine; R10 is chlorine; R3is bromine; R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 422 includes: W is oxygen; R5 is hydrogen; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is hydrogen; R10 is chlorine;R3 is hydrogen; R11 is hydrogen; R4 is NO2; a is 1, n is 1.

Compound 222 includes: W is oxygen; R5 is bromine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is bromine; R10 is hydrogen; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 239 includes: W is oxygen; R5 is bromine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is bromine; R10 is chlorine; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 277-3 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is sulfur; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 278-2 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is sulfur; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is bromine; R10 is chlorine; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 422 includes: W is oxygen; R5 is hydrogen; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is hydrogen; R10 is chlorine;R3 is hydrogen; R11 is hydrogen; R4 is NO2; a is 1, n is 1.

Compound 381 includes: W is oxygen; R5 is chlorine; X is —CH(CH₃)—; R6is hydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen;R1 is —CO2H; R9 is hydrogen; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 382 includes: W is oxygen; R5 is bromine; X is —CH(CH₃)—; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is bromine; R10 is chlorine; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 385 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 2-methyl; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 420 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-O-trifluoromethoxy; R2 is bromine; R10 is chlorine; R3is bromine; R11 is hydrogen; R4 is bromine; a is 1, n is 1. Compound 419includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 is hydrogen; Y isoxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1 is —CO2H; R9 is3-O-trifluoromethoxy; R2 is chlorine; R10 is chlorine; R3 is chlorine;R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 414 includes: W is oxygen; R5 is bromine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is bromine; R10 is hydrogen;R3 is bromine; R11 is hydrogen; R4 is bromine; a is 2, n is 1.

Compound 413 includes: W is oxygen; R5 is chlorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is chlorine; R10 ishydrogen; R3 is chlorine; R11 is hydrogen; R4 is chlorine; a is 2, n is1.

Compound 393 includes: W is oxygen; R5 is —NO2; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is hydrogen; R10 is chlorine; R3is hydrogen; R11 is hydrogen; R4 is hydrogen; a is 1, n is 1.

Compound No 390 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is bromine; R10 is chlorine; R3 isbromine; R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 389 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is chlorine; R10 is chlorine; R3is chlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 386 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 2-methyl; R2 is bromine; R10 is chlorine; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 268 includes: W is hydrogen; R5 is chlorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is absent; R2 is chlorine; R10 is −0-phenyl; R3 ischlorine; R11 is hydrogen; R4 is chlorine; A is 0, n is 0.

Compound 253 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound No 278-2 includes: W is oxygen; R5 is bromine; X is —CH2-; R6is hydrogen; Y is sulfur; R7 is hydrogen; Z is carbon; R8 is hydrogen;R1 is —CO2H; R9 is hydrogen; R2 is bromine; R10 is chlorine; R3 isbromine; R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 277-3 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is sulfur; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 268 includes: W is hydrogen; R5 is chlorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is absent; R2 is chlorine; R10 is −0-phenyl; R3 ischlorine; R11 is hydrogen; R4 is chlorine; A is 0, n is 0.

Compound DHD-251 includes: W is oxygen; R5 is fluorine; X is —CH2-; R6is hydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen;R1 is —CO2H; R9 is hydrogen; R2 is fluorine; R10 is chlorine; R3 isfluorine; R11 is hydrogen; R4 is fluorine; a is 1, n is 1.

Compound 387 includes: W is oxygen; R5 is hydrogen; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is hydrogen; R10 is chlorine; R3is hydrogen; R11 is hydrogen; R4 is hydrogen; a is 1, n is 1.

Compound 412 includes: W is oxygen; R5 is fluorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is fluorine; R10 ishydrogen; R3 is fluorine; R11 is hydrogen; R4 is fluorine; a is 2, n is1.

Compound 296 includes: W is oxygen; R5 is hydrogen; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is hydrogen; R10 is chlorine; R3 is—CONH-(2-methoxy-4-nitro)phenyl; R11 is hydrogen; R4 is hydrogen; a is1, n is 1.

Compound 253 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is hydrogen; R2 is chlorine; R10 is chlorine; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound No 418 includes: W is oxygen; R5 is fluorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethoxy; R2 is fluorine; R10 is chlorine; R3is fluorine; R11 is hydrogen; R4 is fluorine; a is 1, n is 1.

Compound 417 includes: W is oxygen; R5 is hydrogen; X is —CH₂-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethoxy; R2 is hydrogen; R10 is chlorine; R3is hydrogen; R11 is hydrogen; R4 is hydrogen; a is 1, n is 1.

Compound 412 includes: W is oxygen; R5 is fluorine; X is absent; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3,5-di(trifluoromethyl); R2 is fluorine; R10 ishydrogen; R3 is fluorine; R11 is hydrogen; R4 is fluorine; a is 2, n is1.

Compound 388 includes: W is oxygen; R5 is fluorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is fluorine; R10 is chlorine; R3is fluorine; R11 is hydrogen; R4 is fluorine; a is 1, n is 1.

Compound 365 includes: W is oxygen; R5 is bromine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is nitrogen; R8 is absent; R1is —CO2H; R9 is hydrogen; R2 is bromine; R10 is hydrogen; R3 is bromine;R11 is hydrogen; R4 is bromine; a is 1, n is 1.

Compound 364 includes: W is oxygen; R5 is chlorine; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is nitrogen; R8 is absent; R1is —CO2H; R9 is hydrogen; R2 is fluorine; R10 is hydrogen; R3 ischlorine; R11 is hydrogen; R4 is chlorine; a is 1, n is 1.

Compound 387 includes: W is oxygen; R5 is hydrogen; X is —CH2-; R6 ishydrogen; Y is oxygen; R7 is hydrogen; Z is carbon; R8 is hydrogen; R1is —CO2H; R9 is 3-trifluoromethyl; R2 is hydrogen; R10 is chlorine; R3is hydrogen; R11 is hydrogen; R4 is hydrogen; a is 1, n is 1.

Table 2. Compounds of Formula III.

Compound 319 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 isfluorine; R9 is —(CH₂)9CH₃; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 329 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —(CH₂)9CH₃; R3 is bromine; R7 is hydrogen; R4 isbromine; R8 is hydrogen.

Compound 271 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is fluorine; R9 is —(CH₂)7CH₃; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 279-2 includes: W is oxygen; R5 is hydrogen; Y is sulfur; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH₂)7CH₃; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 280-2 includes: W is oxygen; R5 is chlorine; Y is sulfur; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CS2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 201 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2Na; R8 is hydrogen; R2is bromine; R9 is hydrogen; R3 is bromine; R10 is cyano; R4 is bromine;R11 is hydrogen.

Compound 281-2 includes: W is oxygen; R5 is bromine; Y is sulfur; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —COSH; R8 is hydrogen; R2is bromine; R9 is —(CH₂)7CH₃; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 289 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is fluorine; R9 is —(CH₂)15CH3; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 290 includes; W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)15CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 300 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH₂)7CH₃; R3 is hydrogen; R10 is chlorine; R4 ishydrogen; R11 is hydrogen.

Compound 301 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH₂)7CH₃; R3 is hydrogen; R10 is chlorine; R4 ishydrogen.

Compound 302 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is chlorine; R4 ischlorine; R11 is hydrogen.

Compound 318 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 ishydrogen; R9 is —(CH₂)9CH₃; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 303 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —(CH₂)7CH₃; R3 is bromine; R10 is chlorine; R4 isbromine; R11 is hydrogen.

Compound 302 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is chlorine; R4 ischlorine; R11 is hydrogen.

Compound 346 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is absent; R2is bromine; R9 is —(CH₂)7CH₃; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 355 includes; W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —CH₂CH(OH)CH₂OCH₂-(cyclopropyl); R3 is chlorine; R10is chlorine; R4 is chlorine; R11 is hydrogen.

Compound 358 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is oxygen; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 360 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R6 is hydrogen; R1 is —CO2H; R7 is hydrogen; R2is bromine; R9 is —(CH₂)7CH₃; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 223 includes: W is —CH2-; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —OH; R3 is bromine; R10 is hydrogen; R4 is bromine;R11 is hydrogen.

Compound 201 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2Na; R8 is hydrogen; R2is bromine; R9 is hydrogen; R3 is bromine; R10 is cyano; R4 is bromine;R11 is hydrogen.

Compound 89 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is chlorine; R3 is bromine; R10 is trifluoromethyl; R4 isbromine; R11 is hydrogen.

Compound 270 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH₂)7CH₃; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 265 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 252 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2Na; R8 is hydrogen; R2is bromine; R9 is —OH; R3 is bromine; R10 is chlorine; R4 is bromine;R11 is hydrogen.

Compound 345 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is absent; R2is chlorine; R9 is —(CH₂)7CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 307 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 isbromine; R9 is —(CH₂)7CH₃; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 301 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is fluorine; R9 is —(CH₂)7CH₃; R3 is fluorine; R10 is chlorine; R4 isfluorine; R11 is hydrogen.

Compound 300 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH₂)₇CH₃; R3 is hydrogen; R10 is chlorine; R4 ishydrogen; R11 is hydrogen.

Compound 291 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —(CH₂)₁₅CH₃; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 290 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)₁₅CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 280-2 includes: W is oxygen; R5 is chlorine; Y is sulfur; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CS2H; R8 is hydrogen; R2is chlorine; R9 is —(CH₂)₇CH₃; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 279-2 includes: W is oxygen; R5 is hydrogen; Y is sulfur; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH2)7CH3; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 274 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —(CH2)7CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 271 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is fluorine; R9 is —(CH2)7CH3; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 333 includes: W is carbonyl; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —O(CH2)3CH3; R3 is chlorine; R10 is hydrogen; R4 ischlorine; R11 is hydrogen.

Compound 307 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 isbromine; R9 is —(CH2)7CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 288 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH2)15CH3; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 86 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is —NO2; R9 is chlorine; R3 is hydrogen; R10 is trifluoromethyl; R4 ishydrogen; R11 is hydrogen.

Compound 262 includes: W is absent; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is hydrogen; R3 is chlorine; R10 is —CH₂OH; R4 ischlorine; R11 is hydrogen.

Compound 85 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is chlorine; R1 is —CO2H; R8 is hydrogen; R2is —NO2; R9 is hydrogen; R3 is hydrogen; R10 is trifluoromethyl; R4 ishydrogen; R11 is hydrogen.

Compound 257 includes: W is absent; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is chlorine; R3 is chlorine; R10 is methyl; R4 ischlorine; R11 is hydrogen.

Compound 346 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is absent; R2is bromine; R9 is —(CH2)7CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 316 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 isbromine; R9 is —(CH2)9CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 291 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —(CH2)15CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 270 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH2)7CH3; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 356 includes: W is oxygen; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —CH₂CH(OH)CH₂OCH₂-(cyclopropyl); R3 is bromine; R10 ischlorine; R4 is bromine; R11 is hydrogen.

Compound 305 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ismethyl; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2 isfluorine; R9 is —(CH2)7CH3; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 254 includes: W is —CH2-; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —OH; R3 is chlorine; R10 is hydrogen; R4 is chlorine;R11 is hydrogen.

Compound 196 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is hydrogen; R3 is bromine; R10 is trifluoromethyl; R4 isbromine; R11 is hydrogen.

Compound 93 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is chlorine; R3 is hydrogen; R10 is trifluoromethyl; R4is methyl; R11 is hydrogen.

Compound 92 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is chlorine; R3 is methyl; R10 is trifluoromethyl; R4 ishydrogen; R11 is hydrogen.

Compound 86 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is —NO2; R9 is chlorine; R3 is hydrogen; R10 is trifluoromethyl; R4 ishydrogen; R11 is hydrogen.

Compound 350 includes: W is oxygen; R5 is chlorine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is chlorine; R9 is —CH2CH(OH)CH2O(CH2)3CH3; R3 is chlorine; R10 ischlorine; R4 is chlorine; R11 is hydrogen.

Compound 344 includes: W is oxygen; R5 is fluorine; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is absent; R2is fluorine; R9 is —(CH2)7CH3; R3 is fluorine; R10 is hydrogen; R4 isfluorine; R11 is hydrogen.

Compound 343 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is nitrogen; R7 is hydrogen; R1 is —CO2H; R8 is absent; R2is hydrogen; R9 is —(CH2)7CH3; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 334 includes: W is carbonyl; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is —O(CH2)3CH3; R3 is bromine; R10 is hydrogen; R4 isbromine; R11 is hydrogen.

Compound 288 includes: W is oxygen; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is —(CH2)15CH3; R3 is hydrogen; R10 is hydrogen; R4 ishydrogen; R11 is hydrogen.

Compound 232 includes: W is absent; R5 is bromine; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is bromine; R9 is chlorine; R3 is bromine; R10 is methyl; R4 is bromine;R11 is hydrogen.

Compound 47 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is hydrogen; R3 is hydrogen; R10, R11, and the atoms inbetween form a fused 3-hydroxyphenyl; R4 is hydrogen.

Compound 44 includes: W is absent; R5 is hydrogen; Y is oxygen; R6 ishydrogen; Z is carbon; R7 is hydrogen; R1 is —CO2H; R8 is hydrogen; R2is hydrogen; R9 is chlorine; R3 is hydrogen; R10 is trifluoromethyl; R4is hydrogen; R11 is hydrogen.

Table 3. Compounds of Formula IV.

Compound 277-2 includes: W is sulfur; X is sulfur; Y is oxygen; Z is—CH2-; R1 is chlorine; R6 is hydrogen; R2 is chlorine; R7 is -phenyl; R3is chlorine; R8 is chlorine; R4 is chlorine; R9 is hydrogen; R5 ishydrogen.

Compound 280-1 includes: W is oxygen; X is sulfur; Y is oxygen; Z isabsent; R1 is chlorine; R6 is hydrogen; R2 is chlorine; R7 is—(CH2)7CH3; R3 is chlorine; R8 is hydrogen; R4 is chlorine; R9 ishydrogen; R5 is hydrogen.

Compound 281-1 includes: W is oxygen; X is sulfur; Y is oxygen; Z isabsent; R1 is bromine; R6 is hydrogen; R2 is bromine; R7 is —(CH2)7CH3;R3 is bromine; R8 is hydrogen; R4 is bromine; R9 is hydrogen; R5 ishydrogen.

Compound 280-1 includes: W is oxygen; X is sulfur; Y is oxygen; Z isabsent; R1 is chlorine; R6 is hydrogen; R2 is chlorine; R7 is—(CH2)7CH3; R3 is chlorine; R8 is hydrogen; R4 is chlorine; R9 ishydrogen; R5 is hydrogen.

Compound 277-2 includes: W is sulfur; X is sulfur; Y is oxygen; Z is—CH2-; R1 is chlorine; R6 is hydrogen; R2 is chlorine; R7 is -phenyl; R3is chlorine; R8 is chlorine; R4 is chlorine; R9 is hydrogen; R5 ishydrogen.

Table 4. Compounds of Formula V.

Compound 323 includes: X is oxygen; R₆ is hydrogen; Y is oxygen; R₇ ishydrogen; R₁ is —CO₂H; R₈ is hydrogen; R₂ is hydrogen; R₉ is—COO(CH₂)₃CH₃; R₃ is hydrogen; R₁₀ is hydrogen; R₄ is hydrogen; R₁₁ ishydrogen; R₅ is hydrogen.

Compound 324 includes: X is sulfur; R₆ is hydrogen; Y is oxygen; R₇ ishydrogen; R₁ is —CO2H; R₈ is hydrogen; R₂ is hydrogen; R₉ is—COO(CH₂)₃CH₃; R₃ is hydrogen; R₁₀ is hydrogen; R₄ is hydrogen; R₁₁ ishydrogen; R₅ is hydrogen.

Table 5. Compounds of Formula VI.

Compound 126 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is—C(CH₂OH)CH₂CH₃.

Compound 127 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is—C(CH₂OH)CHOH-phenyl.

Compound 118 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is3-(acetoxymethyl)-7-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Compound 138 includes: X is nitrogen; R₃ is —C(CH₂OH)CHOH-phenyl; R₁ andR₂ together form carbonyl.

Compound 119 includes: X is methoxy; R₂ is absent; R₁ is —CO2H; R₃ isabsent.

Compound 120 includes: X is amino; R₂ is absent; R₁ is —CO₂H; R₃ isabsent.

Compound 121 includes: X is hydroxyl; R₂ is absent; R₁ is —CO₂H; R₃ isabsent.

Compound 123 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is—CH₂CHOHCH₃.

Compound 128 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is—C(CH₂OH)CHOH-phenyl.

Compound 129 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂Na; R₃is —C(CH₂OH)CHOHCH₃.

Compound 140 includes: X is nitrogen; R₃ is—C(CH₂OH)CHOH-(4-nitrophenyl); R₁ and R₂ together form carbonyl.

Compound 427 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is-(3-chloro-4-(3-trifluoromethylphenyl)benzyl).

Compound 133 includes: X is nitrogen; R₂ is methyl; R₁ is —CO₂H; R₃ is—CH(CH₃)CHOH-phenyl.

Compound 134 includes: X is nitrogen; R₂ is —(CH₂)₂OH; R₁ is —CO₂H; R₃is —CH(CH₃)-phenyl.

Compound 135 includes: X is nitrogen; R₂ is methyl; R₁ is —CO₂H; R₃ is—CH(CH₃)CHOH-phenyl.

Compound 136 includes: X is nitrogen; R₂ is —(CH₂)₂OH; R₁ is —CO2H; R₃is —CH(CH₃)-phenyl.

Compound 138 includes: X is nitrogen; R₃ is —C(CH₂OH)CHOH-phenyl; R₁ andR₂ together form carbonyl.

Compound 139 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂H; R₃ is—C(CH₂OH)CHOH-(4-nitrophenyl).

Compound 140 includes: X is nitrogen; R₃ is—C(CH₂OH)CHOH-(4-nitrophenyl); R₁ and R₂ together form carbonyl.

Compound 141 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂Na; R₃is —(CH₂)₃SO₃Na.

Compound 142 includes: X is nitrogen; R₃ is —(CH₂)₃SO₃Na; R₁ and R₂together form carbonyl.

Compound 143 includes: X is nitrogen; R₂ is hydrogen; R₁ is —CO₂Na; R₃is —C(CH₂OH)CHOH-(4-nitrophenyl).

Compound 144 includes: X is nitrogen; R₃ is—C(CH₂OH)CHOH-(4-nitrophenyl); R₁ and R₂ together form carbonyl.

Compound 145 includes: X is nitrogen; R₃ is —C(CO2H)CH₂-(4-nitrophenyl);R₁ and R₂ together form carbonyl; and Compound 146 includes: X isnitrogen; R₂ is hydrogen; R₁ is —CO2Na; R₃ is—C(CO₂Na)CH₂-(4-hydroxyphenyl).

Table 6. Compounds of Formula VII.

Compound 95 includes: X is absent; R₄ is hydrogen; R₁ is hydrogen; R₅,R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl; R₂, R₃, and the atoms in between forma 3-methylcyclohexyl.

Compound 96 includes: X is absent; R₄ is hydrogen; R₁ is hydrogen; R₅,R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl; R₂, R₃, and the atoms in between forma 4-methylcyclohexyl.

Compound 94 includes: X is absent; R₄ is hydrogen; R₁ is hydrogen; R₅,R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl; R₂, R₃, and the atoms in between forma cyclohexyl.

Compound 100 includes: X is absent; R₃ is phenyl; R₁ is hydrogen; R₄ isabsent; R₂ is hydrogen; R₅, R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl.

Compound 253 includes: X is absent; R₃ is hydrogen; R₁ is absent; R₄ isabsent; R₂ is hydrogen; R₅, R₆, R₇, and the atom in between form a-4-(N-morpholino)phenyl.

Compound 243 includes: X is —CH₂-; R₄ is hydrogen; R₂, R₃, and the atomsin between form a 1-cyclopentyl; R₅, R₆, R₇, and the atom in betweenform a -3-chloro-4-(O-benzyl)phenyl; R₃ is hydrogen.

Compound 246 includes: X is —CH₂—; R₄ is hydrogen; R₁ and R₂ togetherform a cyclopentyl group; R₅, R₆, R₇, and the atom in between form a-3-trifluoromethyl-4-chlorophenyl; R₃ is hydrogen.

Compound 97 includes: X is absent; R₃ is —OCO-phenyl; R₁ is hydrogen; R₄is hydrogen; R₂ is —OCO-phenyl; R₅, R₆, R₇, and the atom in between forma -3-trifluoromethyl-4-chlorophenyl.

Compound 158 includes: X is absent; R₅ is —CH₂CH₃; R₁ is hydrogen; R₆ ishydrogen; R₂, R₃, and the atoms in between form a 3-methylcyclohexyl; R₇is —CH₂OH; R₄ is hydrogen.

Table 7. Compounds of Formula VIII.

Compound 217 includes: R₁ is bromine; R₄ is bromine; R₂ is bromine; R₅is methyl; R₃ is bromine; R₆ is hydrogen.

Compound 267 includes: R₁ is chlorine; R₄ is chlorine; R₂ is chlorine;R₅ is hydroxyl; R₃ is chlorine; R₆ is 4-nitrophenyl.

Compound 238 includes: R₁ is bromine; R₄ is bromine; R₂ is bromine; R₅is hydroxyl; R₃ is bromine; R₆ is 4-nitrophenyl.

Table 8. Compounds of Formula IX. Compound 108 includes: R₁ is—OCO-phenyl; R₂ is —OCO-phenyl. Compound 109 includes: R₁ is —OCOCH₃; R₂is —OCOCH₃. Compound 110 includes R₁ and R₂ together form a benzene ringthat is substituted with carboxy (—CO₂H). Compound 111 includes: R₁ andR₂ together form a benzene ring that is substituted with carboxy.Table 9. Compounds of Formula X. Compounds of Formula X include thecompounds illustrated in FIGS. 17 and 18, where n is 1, 2, 3, or 4, andR is hydroxy, halo, (C₁-C₈)alkyl, (C₆-C₁₄)aryl, nitro, cyano,(C₁-C₈)alkoxy, trifluoromethyl, or trifluoromethoxy, according tovarious embodiments.

Tables 1-9 above recite certain specific values for various compounds ofFormulas II-X. In some embodiments, a variable “R” (e.g., R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and the like), “W”, “X”, “Y”, or“Z” that is used in connection with one compound or formula may be usedin connection with any other formula described herein to provide othercompounds of the invention. For example, in some embodiments, onespecific halo group can be any halo group, or it can be exchanged foranother specific halo group.

In addition to the exchange of various specific groups described above,organic moieties of the formulas may be optionally substituted with 1,2, 3, 4, or 5 substituents, as would be readily recognized by oneskilled in the art of synthetic organic chemistry. Accordingly, in someembodiments, an alkyl, cycloalkyl, aryl, heteroaryl, or cycloalkyl groupof a formula described herein can optionally be substituted with one ormore (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents. Suitablesubstituents of a substituted group can include alkyl, alkenyl, alkynyl,alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino,dialkylamino, trifluoromethylthio, difluoromethyl, acetylamino, nitro,trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo,alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,heteroarylsulfinyl, heteroarylsulfonyl, heterocyclesulfinyl,heterocyclesulfonyl, phosphate, sulfate, hydroxyl amine, cyano, as wellas —X, —R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN,—N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)₂O—,—S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)(OR₂),—P(═O)(OR₂), —P(═O)(O^(—))₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR, —C(O)O⁻,—C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, and/or —C(NR)NRR, whereeach X is independently halo (F, Cl, Br, or I); and each R isindependently H, alkyl, aryl, heteroaryl, heterocycle, a protectinggroup or prodrug moiety. In some embodiments, specific substituents canbe excluded from a particular formula as well.

Methods of Using the Compounds Described Herein:

The invention provides compositions that include an active ingredient(e.g., a compound as described herein) capable of inhibitingmicroorganisms such as bacteria, particularly vancomycin-resistantbacteria. The invention also provides methods for screening andidentifying these active ingredients.

In one embodiment, the method for screening and identifying anantibacterial compound comprises selecting agents having affinity forone or more penicillin-binding proteins (PBPs) present on the surface ofbacteria. For example, such PBPs are found on a class of bacteria knownin the phylum, Firmicutes. By way of example, member bacteria withinthis phylum include Bacillus (such as Bacillus anthracis), Listeria,Staphylococcus (such as Staphylococcus aureus), Streptococcus,Enterococcus, Clostridium, and Mycobacterium (such as Mycobacteriumtuberculosis).

The invention thus provides a method for selecting compounds that arecapable of binding, and therefore, inhibiting, bacterial species linkedto disease, and thereby inhibit and or eliminate bacterial infection.Among other advantages, the methods provide a technique for identifyingspecific antibacterial compounds and classes of compounds that bind tostrains of bacteria that have become resistant to conventionalpharmaceutical agents.

Several functional assays have been used in the present screening andselection methods, including in vitro screening methods that demonstratethe activity of the compound against vancomycin-resistant, methicillinresistant Staphylococcus aureus. Since PBPs are related to otherproteins of interest in bacteria, the methodology is versatile inscreening for additional activities. These activities include inhibitingβ-lactamase enzymes. β-Lactamases are responsible for bacterialresistance to β-lactam antibiotics. For example, β-lactamases candestroy the activity of β-lactam antibiotics such as penicillins andcephalosporins, etc. If these deleterious enzymes are inhibited,β-lactam antibiotics can be used for treatment of bacterial strains thatharbor β-lactamases. There are four classes of β-lactamases. Class B iszinc-dependent. Classes A, C and D are serine-dependent. Representativemembers of class A, C, and D β-lactamases are TEM-1, P99 and OXA-10enzymes, respectively. As described in the Examples below, compounds ofthe invention inhibit these enzymes.

As discussed above, PBP 2a is a factor in converting a standard S.aureus strain into the problematic MRSA. Furthermore, MRSA is also ableto produce its own class A β-lactamase. Both production of theβ-lactamase and PBP 2a are inducible events, mediated by the proteinBlaR (and the related MecR). The surface domain of BlaR is the β-lactamsensor domain and is related structurally to β-lactamases and PBPs.Assays for inhibition of BlaR and PBP2a are described herein. These andother assays have been employed to select the most promising ofcandidates from a library of chemical compounds.

The invention thus provides compounds and compositions that areeffective to inhibit antibiotic-resistant organisms, such as MRSA. Thecompounds and compositions, in some embodiments, can also inhibitpenicillin-binding proteins (PBPs). In some embodiments, thecompositions include one or more compounds, such as one or morecompounds of the Formulas described herein.

A screening method for identifying antibiotics having affinity tobacteria is also disclosed. In some embodiments the method employs as anactive agent a compound of one of the Formulas described herein. Uponselection of a candidate compound from a chemical library of compounds,the selection being based on chemical structure similarity to one of thechemical core structure of Formulas I-X, the compound is assessed foractivity in one or more functional assays that assess biologicalinhibitory activity for a microorganism, such as a bacterial organism.By way of example, such biological inhibitory activity may be assessedthough the use of a TEM assay, P99 assay, OXA10 assay, BlaR assay orPBP2 assay, as described herein and/or as can be carried out bytechniques well known to those of skill in the art.

Compounds of the invention can be formulated into suitablepharmaceutical compositions for administration to subjects, such ashumans, for example, in a biologically compatible form foradministration in vivo. Accordingly, in certain embodiments, apharmaceutical composition is provided that includes compounds asdescribed herein, admixed with a suitable diluent or carrier. Suitablediluents or carriers include saline or aqueous dextrose, for example, a5% aqueous dextrose solution. Such formulations can be prepared so thatthey are isotonic with human fluids, such as blood, or various tissueenvironments. In certain embodiments, it may also be desirable toprepare hypertonic or hypotonic preparations. In other embodiments, thecomposition can be prepared and used for in vitro experimentation, forexample, in various screens and diagnostic procedures.

Methods for preparing pharmaceutically acceptable compositions are wellknown in the art. The compositions containing a compound as describedherein and a pharmaceutically acceptable vehicle. Suitable vehicles aredescribed, for example, in Remington's Pharmaceutical Sciences (2003,20^(th) Ed.), in The United States Pharmacopeia: The National Formulary(USP 24 NF19) published in 1999, and in the Handbook of PharmaceuticalAdditives (compiled by Michael and Irene Ash, Gower Publishing Limited,Aldershot, England (1995)). On this basis, the compositions include,albeit not exclusively, solutions of the compounds in association withone or more pharmaceutically acceptable vehicles or diluents, as well asbuffered solutions with a suitable pH that are iso-osmotic withphysiological fluids. In this regard, reference can be made to U.S. Pat.No. 5,843,456 (Paoletti et al.).

The compounds described herein can be administered to a subject in avariety of forms depending on the route of administration selected, asis readily understood by those of skill in the art. The compounds can beadministered, for example, by oral, parenteral, buccal, sublingual,nasal, rectal, patch, pump, or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, intrasternal, transepithelial, nasal, intrapulmonary,intrathecal, rectal and infusion modes of administration. Parenteraladministration may be carried out by continuous infusion over a selectedperiod of time.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents can also be useful.

A compound may be orally administered, for example, with an inertdiluent or with an assimilable edible carrier, or it may be enclosed inhard or soft shell gelatin capsules, or it may be compressed intotablets, or it may be incorporated directly with the food of the diet.For oral therapeutic administration, the compound of the invention maybe incorporated with excipient and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Solutions of a compound can be prepared inwater suitably mixed with suitable excipients. Under ordinary conditionsof storage and use, these preparations may contain a preservative, forexample, to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersion and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. The formulation should be sterile and should be fluid tothe extent that the solution or dispersion can be administered viasyringe.

The compositions described herein can be administered to an animal aloneor in combination with pharmaceutically acceptable carriers, as notedabove, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard pharmaceutical practice. In an embodiment, the pharmaceuticalcompositions are administered in a convenient manner such as by directapplication to the infected site, e.g. by injection (subcutaneous,intravenous, parenteral, etc.). In case of respiratory infections, itmay be desirable to administer the compounds of the invention andcompositions comprising same, through known techniques in the art, forexample by inhalation. Depending on the route of administration (e.g.,injection, oral, or inhalation, etc.), the pharmaceutical compositionsor compounds or biologically active agents in the compounds of theinvention may be coated in a material to protect the compounds or agentsfrom the action of enzymes, acids, and other natural conditions that mayinactivate certain properties of the composition or its encapsulatedagent.

In addition to pharmaceutical compositions, compositions fornon-pharmaceutical purposes are also included within the scope of theinvention. Such non-pharmaceutical purposes may include the preparationof diagnostic or research tools. In one embodiment, the compounds can belabeled with labels known in the art, such as florescent orradio-labels, or the like.

The dosage of the compounds of the invention can vary depending on manyfactors such as the pharmacodynamic properties of the compound, the rateof release of the agent from the delivery composition, the mode ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the frequency of the treatment and the typeof concurrent treatment, if any, and the clearance rate of the agentand/or compound in the subject to be treated.

For example, in some embodiments, a dose of a compound formulationequivalent to about 1 mg mL⁻¹ to about 100 mg mL⁻¹ can be administeredto a patient. In certain other embodiments, the compound formulationincludes about 2-20, about 5-15, or about 10 mg mL⁻¹. The specific dosesof the compounds administered according to this invention to obtaintherapeutic and/or prophylactic effects will, of course, be determinedby the particular circumstances surrounding the case, including, forexample, the compounds administered, the route of administration, thecondition being treated and the individual being treated. A typicaldaily dose (administered in single or in divided doses) can contain adosage level of from about 0.01 mg/kg to about 150 mg/kg of body weightof an active therapeutic agent described herein. In some embodiments,about 5-10, about 10-20, about 20-40, about 25-50, about 50-75, about75-100, or about 100-150 150 mg/kg of body weight of a therapeutic agentare provided in a dose. In other embodiments, about 5, 10, 15, 20, 25,30, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 140, or 150 mg/kg ofbody weight of a therapeutic agent are delivered in a dose. Often times,daily doses generally will be from about 0.05 mg/kg to about 20 mg/kgand ideally from about 0.1 mg/kg to about 10 mg/kg.

The compounds can be used alone or in combination with other agents thattreat the same and/or another condition, disease or disorder. In anotherembodiment, where either or both the compound or biologically activeagent is labeled, one can conduct in vivo or in vitro studies fordetermining optimal dose ranges and drug loading concentrations for thespecific condition.

Other compounds and techniques well known to those of skill in the artthat can be used in conjunction with the compounds and methods describedherein include those described in U.S. Pat. Nos. 7,314,888, 7,259,167,7,141,573, 6,846,953, and 6,583,119.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

The following Examples are intended to illustrate the above inventionand should not be construed as to narrow its scope. One skilled in theart will readily recognize that the Examples suggest many other ways inwhich the invention could be practiced. It should be understood thatnumerous variations and modifications may be made while remaining withinthe scope of the invention.

EXAMPLES Example 1

Preparation of Various Compounds of the Invention.

Compound numbers refer to the corresponding chemical structuresillustrated at the end of this Example. Compounds described herein maybe prepared by the methods analogous to those illustrated below inScheme 14-1 and by following general procedures.

General Procedure for Coupling Reactions:

Step A. To a stirred solution of 2-chloro-4-nitrophenol, (17.3 grams,0.10 mol) and NaH (60% in oil, 5 grams, 0.125 mol) in THF (200 mL) andDMF (30 mL) was added alkyl bromide (0.11 mol). The reaction was stirredfor 2 hours at 45° C. under argon. The resultant mixture wasconcentrated to give an oily residue, which was carefully diluted withwater, and extracted three times with dichloromethane (50 mL). Theorganic layer was washed with 0.1 M hydrochloric acid (HCl), thensuccessively with water, and brine, and dried over anhydrous sodiumsulfate. The resulting organic layer was filtered, and concentrated invacuo to afford a crude material, which was purified via flashchromatography using either silica (230-400 mesh), or activated neutralalumina (Aldrich, Brockmann 1, 150 mesh), eluting with solvent systemsindividually developed for each compound.

Compound 372.

To a stirred solution of 2-chloro-4-nitrophenol (17.3 grams, 0.10 mol)and NaH (60% in oil, 5 grams, 0.125 mol) in THF (200 mL) and DMF (30 mL)is added (3-trifluoromethyl)benzyl bromide (17 mL) at room temperature(r.t.). The reaction mixture is stirred for 2 hours at 45° C. underargon. The resulted mixture is concentrated to give an oily residue,which is dissolved in dichloromethane (50 mL), washed successively with10 mL each of water, 0.1 M hydrochloric acid (HCl), water, saturatedsodium hydrogen carbonate solution and brine, and dried over anhydroussodium sulfate. Sample was isolated by column chromatography usingsilica gel (CH₂Cl₂/Et₂O=1:3) in 86% yield. ¹H NMR (300 MHz, DMSO-d₆) δppm 5.49 (s, 2H), 7.49 (d, J=9.1 Hz, 1H), 7.66-7.79 (m, 2H), 7.79-7.84(m, 1H), 7.89 (s, 1H), 8.27 (dd, J=9.1, 2.7 Hz, 1H), 8.32-8.36 (m, 1H).¹³C NMR (75 MHz, DMSO-d₆) δ ppm 70.1, 113.8, 122.1, 124.1, 124.1, 124.6,125.0, 125.4, 129.8, 131.6, 137.1, 141.0, 158.6.

General Procedure for the Reductions:

Step B) Using SnCl₂. A solution of the starting nitro derivative (e.g.,compound 372, 1.3 mmol), and stannous chloride dihydrate (1.1 grams, 4.4mmol) in EtOH (15 mL) was heated at 70° C. for 2-4 hours. The solventwas removed under reduced pressure and the residue diluted with 20-30%aqueous NaOH. The aqueous layer was extracted with organic solvents. Theorganic extract were washed with saturated aqueous NaCl, dried (MgSO₄),filtered, and concentrated under reduced pressure to afford acorresponding crude amino derivative, which was further purified bycolumn chromatography or introduced into the next reaction step withoutfurther purification.

Step B) Using Pd/C—H₂. A stirred solution of nitro compound (0.1 mol) inMeOH (400 mL), was cautiously treated with Pd/C (10%, 2 grams), and thenkept under an atmosphere of hydrogen with continued stirring at roomtemperature overnight. The mixture was diluted with MeOH (200 mL) andfiltered through a layer of Celite, and the Celite pad was washed withMeOH. The volatiles were evaporated in vacuo to afford a correspondingamino derivative, which was introduced into the next reaction stepwithout further purification.

Compound 378.

A homogenous solution of derivative 372 (24 grams, 0.072 mol) andstannous chloride dihydrate (53 grams, 0.24 mol) in EtOH (400 mL) washeated at 70° C. for 1 hour. The solvent was removed under reducedpressure and the residue diluted with 20-30% aqueous NaOH to raise thepH to about 9. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic extracts were washed with saturated aq. NaCl, dried (MgSO₄),filtered, and concentrated under reduced pressure to afford a crudematerial, which was further purified by silica gel column chromatography(CH₂Cl₂/n-Hexane=6:1) to afford compound 378 in 79% yield. 1H NMR (500MHz, CDCl₃) δ ppm 3.48 (s, 2H), 5.06 (s, 2H), 6.50 (dd, J=8.7, 2.7 Hz,1H), 6.72-6.81 (m, 2H), 7.47-7.51 (m, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.65(d, J=7.7 Hz, 1H), 7.74 (s, 1H). ¹³C NMR (126 MHz, CDCl₃) δ ppm 71.6,114.3, 117.1, 117.1, 123.1, 124.0, 124.0, 124.0, 124.1, 124.5, 124.7,124.7, 124.7, 124.8, 125.3, 128.9, 129.1, 130.6, 130.9, 138.2, 141.9,146.7.

General Procedure for Coupling Terminal Amines and Phthalic Anhydrides:

Step C. A round-bottom flask was charged with substituted phthalicanhydrides (1 equiv), aryl- or alkyl amine (1.05-1.10 equiv), THF anddry triethylamine (0.1 equiv). For some sequences, DMF was used as acosolvent due to poor solubility of the reactants. The concentrations ofthe reactions varied from 0.3 to 0.1 M depending on the solubility ofthe reactants. The flask was then evacuated and backfilled withnitrogen, sealed with a cap, and stirred at 30° C. for 1-12 hours. Thedisappearance of starting materials may be monitored by Thin LayerChromatography. After completion, the solvent was removed and thereaction mixture was purified by flash column chromatography.

Compound 390.

To a solution of compound 378 (3.17 grams, 0.010 mol) in THF (80 mL),Et₃N (0.1 mL) was added a solution of 3,4,5,6-tetrabromophthalicanhydride (5.0 grams, 0.011 mol) dissolved in dry DMF (30 mL). Thereaction mixture was flushed with nitrogen, and the reaction vessel wasclosed, and stirred at 30° C. for 6 hours. The organic solvents wereevaporated. The residue was chromatographed on silica gel (CH₂Cl₂/MeOH,5:1) as eluent and was further purified by recrystallization from amixture of CH₃CN/H₂O to give 390 as yellowish powder in 76% yield. 1HNMR (500 MHz, DMSO-d6) δ ppm 5.31 (s, 2H), 7.27 (d, J=8.7 Hz, 1H), 7.43(dd, J=8.9, 1.4 Hz, 1H), 7.64-7.73 (m, 2H), 7.77 (d, J=6.9 Hz, 1H),7.80-7.86 (m, 2H), 10.77 (s, 1H). ¹³C NMR (126 MHz, DMSO-d6) δ ppm 69.9,115.4, 116.3, 119.9, 121.6, 122.1, 123.4, 124.3, 125.2, 130.1, 130.8,131.8, 133.0, 138.1, 138.6, 150.4, 166.3.

The Substituted 2,3-Dihydro[1,4]dithiino Phthalimides Were Prepared bythe Following General Method.

Step D). 2,3-Dihydro[1,4]dithiino[2,3-c]furan-5,7-dione (1.88 grams,0.01 mol) and (1S,2S)-2-amino-1-(4nitrophenyl)propane-1,3-diol (2.10grams, 0.01 mol) were added to DMF (10 mL). The mixture was heated withstirring to 60° C. for 1 hour. At this point the majority of thestarting material had been converted into the 2,3-dihydro[1,4]dithiinophthalimide derivative 140. The reaction mixture was then evaporated andthe crude product poured into water to remove any remaining DMF. Theresulting material was further purified by column chromatography to give140 in high yield. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.00-3.10 (m, 1H),3.41 (s, 4H), 3.80 (td, J=10.8, 5.7 Hz, 1H), 4.06 (td, J=9.9, 4.2 Hz,1H), 4.82 (t, J=5.9 Hz, 1H), 4.99 (dd, J=9.5, 4.3 Hz, 1H), 5.95 (d,J=4.4 Hz, 1H), 7.65 (d, J=8.6 Hz, 2H), 8.24 (d, J=8.6 Hz, 2H). ¹³C NMR(126 MHz, DMSO-d6) δ ppm 25.2, 26.0, 57.5, 60.2, 67.0, 69.2, 95.4,123.6, 128.1, 147.1, 150.4, 167.1.

The Substituted 2,3-Dihydro[1,4]dithiino Carbamoyl Derivatives WerePrepared by the Following General Method

Step E) A solution of previously synthesized imide derivative 140 (2.45grams, 0.01 mol) was treated with 2 equiv of K₂CO3 in 50% EtOH (100 mL)at room temperature. With continued stirring, the resultant solution wasallowed to warm to 30° C., and stirred for 4-5 hours to completedisappearance of the starting material. After filtration a few drops ofdiluted aqueous HCl were added before the solvents were removed in vacuoand the residue was chromatographed (CH₂Cl₂/MeOH, 4:1) to give 2.9 grams(68%) of the corresponding potassium3-((1S,2S)-1,3-dihydroxy-1-(4-nitrophenyl)propane-2-ylcarbamoyl)-5,6-dihydro1,4-dithiine-2-carboxylate (Compound139) as a yellow solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 3.12-3.20 (m, 4H),3.63-3.69 (m, 1H), 3.69-3.76 (m, 1H), 4.12 (dd, J=9.9, 5.8 Hz, 1H), 5.05(d, J=3.5 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 8.17 (d, J=8.6 Hz, 2H). In asimilar fashion, the following compounds were prepared.

Compound 7. ¹H NMR (300 MHz, CD₃OD) δ ppm 4.55 (s, 2H), 7.17-7.27 (m,1H), 7.43-7.57 (m, 5H), 7.69-7.76 (m, 1H), 7.82 (d, J=6.7 Hz, 1H), 8.40(d, J=4.3 Hz, 1H).

Compound 8. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=7.3 Hz, 1H),7.54-7.61 (m, 3H), 7.64-7.70 (m, 1H), 7.84-7.93 (m, 2H), 8.22 (s, 1H),10.69 (s, 1H), 13.14 (s, 1H).

Compound 11. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.76-1.86 (m, 4H), 3.09 (t,J=6.4 Hz, 2H), 3.53 (t, J=6.7 Hz, 2H), 7.18 (d, J=6.1 Hz, 1H), 7.98 (d,J=7.3 Hz, 1H).

Compound 19. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.21 (t, J=6.9 Hz, 3H), 1.28(t, J=7.3 Hz, 3H), 3.45-3.51 (m, 4H), 6.38 (d, J=13.0 Hz, 1H), 6.61 (d,J=13.0 Hz, 1H).

Compound 20. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.31 (d, J=11.4 Hz, 1H),6.48 (d, J=12.2 Hz, 1H), 7.72 (d, J=8.9 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H),10.60 (s, 1H), 12.84 (s, 1H).

Compound 21. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (s, 2H), 3.01 (s, 2H),3.17 (s, 3H), 3.71 (s, 2H), 6.85 (d, J=3.2 Hz, 3H), 6.89-6.97 (m, 3H),7.31 (d, J=7.3 Hz, 1H), 7.51 (t, J=6.9 Hz, 1H), 7.63 (t, J=6.9 Hz, 1H),7.92 (d, J=6.5 Hz, 1H).

Compound 22. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (t, J=7.3 Hz, 7H),3.23-3.33 (m, 5H), 6.65 (d, J=8.9 Hz, 2H), 7.45-7.56 (m, 5H).

Compound 23. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (d, J=4.1 Hz, 1H),7.59-7.67 (m, 3H), 7.67-7.74 (m, 3H), 7.91 (d, J=7.3 Hz, 1H), 8.38 (d,J=8.1 Hz, 1H), 8.73 (d, J=7.3 Hz, 1H), 8.83 (d, J=4.1 Hz, 1H), 10.15 (s,1H).

Compound 24. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (t, J=6.9 Hz, 2H),7.70 (t, J=7.7 Hz, 1H), 7.79 (s, 1H), 7.93 (d, J=7.3 Hz, 1H), 8.35 (s,2H), 10.99 (s, 1H), 13.20 (s, 1H).

Compound 25. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.66 (s, 3H), 3.76 (s, 4H),6.36 (d, J=8.1 Hz, 1H), 6.52 (s, 1H), 6.73 (d, J=8.9 Hz, 1H), 7.55 (d,J=3.2 Hz, 2H), 7.78 (s, 1H), 7.80 (d, J=5.7 Hz, 2H).

Compound 26. ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.11 (dd, J=17.4, 5.3 Hz,5H), 6.13-6.21 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 7.50-7.58 (m, 2H),7.70-7.76 (m, 2H).

Compound 27. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.37 (m, 1H), 7.43(dt, J=14.6, 7.3 Hz, 3H), 7.57 (t, J=6.9 Hz, 1H), 7.66 (t, J=6.9 Hz,1H), 7.89 (d, J=8.1 Hz, 2H), 10.23 (s, 1H), 13.08 (s, 1H).

Compound 28. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.16 (t, J=7.3 Hz, 1H),7.54-7.66 (m, 4H), 7.72 (s, 1H), 7.84 (t, J=6.5 Hz, 2H), 8.32 (s, 1H),8.59 (d, J=7.3 Hz, 1H), 12.21 (s, 1H).

Compound 29. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 1H), 1.30-1.39 (m,6H), 4.01 (d, J=6.5 Hz, 5H), 7.50-7.61 (m, 8H), 7.78 (d, J=7.3 Hz, 1H),7.95 (d, J=7.3 Hz, 2H).

Compound 30. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.90 (t, J=8.5 Hz, 1H),7.37 (td, J=15.8, 8.1 Hz, 2H), 7.52-7.61 (m, 2H), 7.62-7.71 (m, 2H),7.89 (d, J=8.1 Hz, 1H), 10.55 (s, 1H), 13.10 (s, 1H).

Compound 32. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (t, J=6.9 Hz, 6H),3.24-3.32 (m, 4H), 6.26-6.31 (m, 1H), 6.46-6.52 (m, 1H), 6.63 (d, J=9.7Hz, 2H), 7.43 (d, J=8.9 Hz, 2H), 10.51 (s, 1H).

Compound 33. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (d, J=12.2 Hz, 1H),6.84 (d, J=12.2 Hz, 1H), 7.56-7.66 (m, 2H), 7.69-7.74 (m, 1H), 8.41 (d,J=8.1 Hz, 1H), 8.64 (d, J=7.3 Hz, 1H), 8.92 (s, 1H), 10.58 (s, 1H).

Compound 34. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.33-6.41 (m, 1H),6.46-6.54 (m, 1H), 7.72 (s, 1H), 8.24-8.29 (m, 2H), 10.89 (s, 1H).

Compound 35. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 4H), 3.81 (s, 3H),6.31 (d, J=12.2 Hz, 1H), 6.48-6.53 (m, 1H), 6.63 (s, 2H), 7.72 (d, J=8.9Hz, 1H), 9.91 (s, 1H).

Compound 36. ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.19 (s, 4H), 6.27 (d,J=12.2 Hz, 1H), 6.41 (d, J=12.2 Hz, 1H), 6.79 (d, J=8.9 Hz, 1H), 6.99(d, J=8.9 Hz, 1H), 7.24 (s, 1H), 10.29 (s, 1H).

Compound 37. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.36 (d, J=12.2 Hz, 1H),6.49 (d, J=12.2 Hz, 1H), 7.74 (s, 1H), 8.25 (s, 3H), 10.89 (s, 1H).

Compound 38. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (d, J=12.2 Hz, 1H),6.53 (d, J=11.4 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H),7.74 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 8.28 (s, 1H), 8.43 (d, J=8.1 Hz,1H), 11.91 (s, 1H), 12.95 (s, 1H).

Compound 39. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.38 (m, 8H),3.96-4.06 (m, 6H), 7.50-7.60 (m, 4H), 7.89 (s, 1H), 7.93 (d, J=7.3 Hz,3H).

Compound 40. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.30 (d, J=12.2 Hz, 1H),6.42-6.49 (m, 1H), 6.87-6.93 (m, 1H), 7.28-7.37 (m, 2H), 7.59 (d, J=12.2Hz, 1H), 10.49 (s, 1H), 12.91 (s, 1H).

Compound 41. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.76 (m, 4H),2.67-2.77 (m, 4H), 6.94 (d, J=7.3 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 7.27(d, J=8.1 Hz, 1H), 7.52-7.58 (m, 2H), 7.61-7.69 (m, 1H), 7.86 (d, J=8.1Hz, 1H), 9.60 (s, 1H).

Compound 42. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.22 (s, 2H), 7.06 (s, 2H),7.33-7.42 (m, 4H), 7.53 (t, J=7.3 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.66(d, J=7.3 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 9.83 (s, 1H).

Compound 43. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.04 (d, J=4.9 Hz, 4H),3.66-3.76 (m, 4H), 6.90 (d, J=8.9 Hz, 2H).

7.50-7.57 (m, 4H), 7.61 (d, J=7.3 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 10.11(s, 1H).

Compound 404. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (dd, J=12.2, 7.3 Hz,2H), 7.63-7.71 (m, 2H), 7.91 (d, J=8.1 Hz, 2H), 8.29 (s, 1H), 10.77 (s,1H).

Compound 45. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.53-7.61 (m, 4H), 7.67 (t,J=7.3 Hz, 1H), 7.90 (t, J=6.5 Hz, 2H), 8.17 (s, 1H), 10.69 (s, 1H).

Compound 46. ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.53-7.61 (m, 3H),7.63-7.69 (m, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 8.13(s, 1H), 10.26 (s, 1H).

Compound 47. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.65 (d, J=6.5 Hz, 1H),6.95-7.06 (m, 4H), 7.23 (s, 1H), 7.53-7.62 (m, 4H), 7.69 (d, J=3.2 Hz,3H).

Compound 48. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (t, J=7.7 Hz, 2H),7.53-7.60 (m, 3H), 7.65 (t, J=6.9 Hz, 2H), 7.86 (dd, J=12.2, 8.1 Hz,2H), 8.37 (s, 1H), 10.50 (s, 1H).

Compound 50. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.61 (s, 3H), 3.66 (s, 3H),6.19 (d, J=8.1 Hz, 1H), 6.36 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 7.54 (d,J=3.2 Hz, 2H), 7.56 (s, 1H), 7.73 (s, 1H), 7.74 (d, J=5.7 Hz, 1H).

Compound 51. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (d, J=5.7 Hz, 4H),2.55-2.64 (m, 2H), 2.67-2.75 (m, 2H), 6.28 (d, J=12.2 Hz, 1H), 6.57 (d,J=13.0 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.06 (t, J=7.7 Hz, 1H), 7.21 (d,J=7.3 Hz, 1H), 9.82 (s, 1H).

Compound 52. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.20-6.29 (m, 3H), 6.46 (d,J=12.2 Hz, 1H), 6.97 (s, 2H), 7.31-7.39 (m, 3H), 7.64 (d, J=6.5 Hz, 1H),9.96 (s, 1H).

Compound 53. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.00-3.07 (m, 4H),3.65-3.74 (m, 4H), 6.29 (d, J=12.2 Hz, 1H), 6.43-6.49 (m, 1H), 6.90 (d,J=8.9 Hz, 2H), 7.49 (d, J=8.9 Hz, 2H), 10.42 (s, 1H).

Compound 54. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.30-6.37 (m, 1H), 6.46 (d,J=12.2 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 8.19 (s,1H), 10.68 (s, 1H), 12.89 (s, 1H).

Compound 55. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.32 (d, J=12.2 Hz, 1H),6.44-6.51 (m, 1H), 7.51-7.56 (m, 2H), 7.79 (d, J=4.1 Hz, 1H), 8.09 (s,1H), 10.61 (s, 1H).

Compound 56. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.38 (d, J=12.2 Hz, 1H),6.63 (d, J=12.2 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H),8.24 (s, 1H), 10.25 (s, 1H).

Compound 57. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.39 (d, J=12.2 Hz, 1H),6.70 (d, J=12.2 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 7.22-7.32 (m, 2H), 7.57(d, J=7.3 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 9.84(s, 1H), 10.42 (s, 1H).

Compound 58. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.30 (d, J=11.4 Hz, 1H),6.43-6.50 (m, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.81(d, J=8.1 Hz, 1H), 8.26 (s, 1H), 10.51 (s, 1H).

Compound 59. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (d, J=4.9 Hz, 4H),3.44 (s, 2H), 3.58 (s, 2H), 5.99 (d, J=12.2 Hz, 1H), 6.70 (d, J=12.2 Hz,1H), 6.80 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.95 (s, 1H), 7.21(t, J=8.1 Hz, 1H).

Compound 60. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.71 (d, J=3.2 Hz, 7H),6.28-6.34 (m, 1H), 6.40-6.48 (m, 1H), 6.90 (d, J=8.9 Hz, 1H), 7.12 (d,J=8.1 Hz, 1H), 7.32 (s, 1H), 10.36 (s, 1H).

Compound 81. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.05 (t, J=7.1 Hz, 7H),3.29 (q, J=7.1 Hz, 5H), 6.59-6.66 (m, 2H), 7.44-7.51 (m, 3H), 7.89 (d,J=8.1 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H).

Compound 82. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (s, 1H), 7.88 (t,J=8.1 Hz, 1H), 8.22 (s, 2H), 8.34 (d, J=8.1 Hz, 1H), 8.42 (d, J=8.1 Hz,1H), 11.31 (s, 1H).

Compound 83. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 6H), 6.54 (d,J=8.9 Hz, 1H), 6.60 (s, 1H), 7.74 (t, J=8.1 Hz, 1H), 7.90 (d, J=8.9 Hz,1H), 8.20 (d, J=8.1 Hz, 1H), 8.27 (d, J=8.1 Hz, 1H), 9.78 (s, 1H).

Compound 84. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.25 (t, J=7.3 Hz, 1H),7.37-7.46 (m, 2H), 7.81 (t, J=7.7 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.28(d, J=7.3 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 10.48 (s, 1H).

Compound 86. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (d, J=8.9 Hz, 1H),7.78-7.84 (m, 1H), 7.84-7.88 (m, 1H), 8.18 (s, 1H), 8.32 (d, J=8.1 Hz,1H), 8.38 (d, J=8.1 Hz, 1H), 11.07 (s, 1H).

Compound 87. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.61 (d, J=8.1 Hz, 1H),7.69 (d, J=7.6 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 8.14 (s, 1H), 8.20 (d,J=8.1 Hz, 1H), 8.44 (s, 1H), 10.42 (s, 1H).

Compound 89. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.64 (d, J=7.8 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 8.10 (br. s., 1H), 10.77 (s, 1H).

Compound 92/93. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.42 (d, J=6.2 Hz, 3H),7.34-7.44 (m, 1H), 7.48 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.15 (br. s, 1H), 10.19-10.31 (m, 1H).

Compound 94. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (dd, J=8.8, 3.8 Hz,1H), 1.39-1.54 (m, 2H), 1.54-1.67 (m, 1H), 1.67-1.82 (m, 2H), 1.95-2.13(m, 2H), 2.60-2.78 (m, 1H), 3.09 (d, J=4.8 Hz, 1H), 7.50 (dd, J=8.4, 2.0Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 9.55 (s, 1H).

Compound 95/96. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.83-0.96 (m, 3H), 1.45(dd, J=6.4, 3.4 Hz, 1H), 1.49-1.67 (m, 2H), 1.77-1.96 (m, 2H), 1.96-2.13(m, 1H), 2.56-2.78 (m, 1H), 3.10-3.24 (m, 1H), 7.50 (dd, J=8.5, 2.3 Hz,1H), 7.73 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 9.38 (s, 1H).

Compound 97. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.71 (s, 1H), 5.88 (s, 2H),7.61 (t, J=7.5 Hz, 5H), 7.74 (t, J=7.2 Hz, 3H), 7.89-8.12 (m, 4H), 13.93(br. s, 1H)

Compound 100. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.02 (s, 1H), 7.48-7.52(m, 3H), 7.54-7.59 (m, 2H), 7.77-7.80 (m, 1H), 8.45 (d, J=1.6 Hz, 1H),10.06 (s, 1H).

Compound 108. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.22-4.37 (m, 2H), 5.87(dd, J=19.9, 2.8 Hz, 2H), 6.09 (d, J=2.6 Hz, 1H), 6.18 (dd, J=3.1, 1.9Hz, 1H), 7.58 (dt, J=11.3, 7.8 Hz, 4H), 7.72 (t, J=7.5 Hz, 2H),7.97-8.09 (m, 4H), 9.01 (t, J=5.8 Hz, 1H).

Compound 111. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.43 (d, J=5.6 Hz, 3H),6.32-6.36 (m, 1H), 6.41 (dd, J=3.2, 1.8 Hz, 1H), 7.56-7.62 (m, 1H), 7.84(d, J=8.2 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 8.05 (dd, J=8.0, 1.8 Hz, 1H),9.01 (t, J=5.7 Hz, 1H).

Compound 114. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.94 (d, J=6.6 Hz, 3H),3.18 (d, J=14.2 Hz, 4H), 7.18 (s, 1H), 7.43 (s, 1H

Compound 118. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.01 (s, 3H), 3.23 (d,J=16.9 Hz, 1H), 3.36-3.48 (m, 6H), 4.85 (d, J=12.2 Hz, 1H), 4.98-5.06(m, 2H), 5.61 (d, J=4.8 Hz, 1H).

Compound 119. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (s, 4H), 4.07 (s,4H).

Compound 120. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (s, 4H).

Compound 121. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 4H).

Compound 123. ¹H NMR (400 MHz, D20) δ ppm 1.12 (d, J=6.5 Hz, 2H), 1.19(d, J=6.5 Hz, 2H), 2.84 (dd, J=13.0, 9.7 Hz, 1H), 3.00-3.10 (m, 1H),3.13-3.24 (m, 4H), 3.90-3.95 (m, 1H), 3.99 (d, J=6.5 Hz, 1H).

Compound 124. ¹H NMR (400 MHz, D20) δ ppm 1.15 (d, J=6.5 Hz, 3H),3.18-3.27 (m, 7H), 3.91-4.00 (m, 2H).

Compound 125. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.95 (ddd, J=15.6, 7.6, 7.3Hz, 4H), 1.39-1.54 (m, 1H), 1.67 (dt, J=14.7, 7.3 Hz, 1H), 3.49-3.64 (m,2H), 3.69-3.79 (m, 2H), 3.81-3.92 (m, 1H).

Compound 126a. ¹H NMR (400 MHz, D₂O) δ ppm 0.93 (t, J=7.7 Hz, 3H), 1.45(dd, J=16.2, 7.3 Hz, 1H), 1.57 1.67 (m, 1H), 3.20-3.29 (m, 4H),3.55-3.60 (m, 1H), 3.62-3.68 (m, 1H), 3.75-3.83 (m, 1H).

Compound 127. ¹H NMR (500 MHz, D20) δ ppm 3.03-3.10 (m, 3H), 3.40 (dd,J=11.6, 7.1 Hz, 1H), 3.50 (dd, J=11.6, 5.1 Hz, 1H), 3.98-4.03 (m, 1H),4.76 (d, J=5.6 Hz, 1H), 7.21-7.26 (m, 1H), 7.26-7.30 (m, 5H).

Compound 128. ¹H NMR (400 MHz, D20) δ ppm 3.17 (d, J=8.9 Hz, 3H), 3.20(s, 1H), 3.46-3.54 (m, 1H), 3.54-3.64 (m, 1H), 4.06-4.15 (m, 1H), 4.86(d, J=5.7 Hz, 1H), 7.29-7.36 (m, 1H), 7.36-7.41 (m, 4H).

Compound 129. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.08 (m, 3H), 3.04(s, 1H), 3.10-3.28 (m, 2H), 3.28-3.46 (m, 2H), 3.50 (br. s, 1H), 3.66(br. s, 1H),

Compound 130. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.26 (d, J=5.7 Hz, 4H),2.99-3.07 (m, 1H), 3.19 (s, 2H), 3.63-3.72 (m, 2H), 3.80 (dd, J=11.8,3.6 Hz, 1H), 3.84-3.91 (m, 1H).

Compound 133. ¹H NMR (500 MHz, D20) δ ppm 0.92 (d, J=6.6 Hz, 3H), 2.05(s, 2H), 2.59 (s, 3H), 3.00-3.07 (m, 3H), 4.50 (d, J=9.1 Hz, 1H), 7.22(s, 1H), 7.24-7.32 (m, 5H).

Compound 134. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.56 (d, J=6.7 Hz, 2H),3.01-3.15 (m, 5H), 3.58-3.68 (m, 5H), 4.07-4.18 (m, 3H), 7.22-7.35 (m,3H).

Compound 135. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.99 (d, J=7.1 Hz, 2H), 1.19(t, J=7.3 Hz, 2H), 2.94-3.03 (m, 3H), 3.09-3.18 (m, 3H), 7.15-7.21 (m,1H), 7.22-7.27 (m, 3H), 7.29-7.36 (m, 2H).

Compound 136. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.74 (d, J=7.1 Hz, 3H),3.16-3.19 (m, 2H), 3.20-3.24 (m, 2H), 3.44 (s, 1H), 3.70 (s, 2H),3.79-3.84 (m, 2H), 7.34 (t, J=7.3 Hz, 1H), 7.40 (t, J=7.6 Hz, 2H), 7.51(d, J=7.6 Hz, 2H).

Compound 138. ¹H NMR (500 MHz, ACETONE-d6) δ ppm 1.76-1.82 (m, 3H), 2.05(qd, J=2.2, 2.0 Hz, 1H), 3.62 (t, J=6.8 Hz, 3H), 3.95-4.03 (m, 1H), 4.37(ddd, J=13.4, 4.8, 4.6 Hz, 1H), 5.24-5.29 (m, 1H), 7.74 (d, J=8.6 Hz,2H), 8.25-8.28 (m, 2H).

Compound 139. ¹H NMR (500 MHz, CD₃OD) δ ppm 3.12-3.20 (m, 4H), 3.63-3.69(m, 1H), 3.69-3.76 (m, 1H), 4.12 (dd, J=9.9, 5.8 Hz, 1H), 5.05 (d, J=3.5Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 8.17 (d, J=8.6 Hz, 2H).

Compound 140. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.00-3.10 (m, 1H), 3.41(s, 4H), 3.80 (td, J=10.8, 5.7 Hz, 1H), 4.06 (td, J=9.9, 4.2 Hz, 1H),4.82 (t, J=5.9 Hz, 1H), 4.99 (dd, J=9.5, 4.3 Hz, 1H), 5.95 (d, J=4.4 Hz,1H), 7.65 (d, J=8.6 Hz, 2H), 8.24 (d, J=8.6 Hz, 2H). ¹³C NMR (126 MHz,DMSO-d6) δ ppm 25.2, 26.0, 57.5, 60.2, 67.0, 69.2, 95.4, 123.6, 128.1,147.1, 150.4, 167.1

Compound 141. ¹H NMR (400 MHz, D20) δ ppm 1.89-1.99 (m, 2H), 2.88-2.97(m, 2H), 3.17-3.26 (m, 4H), 3.28-3.32 (m, 1H).

Compound 142. ¹H NMR (500 MHz, D20) δ ppm 1.12 (t, J=7.3 Hz, 9H),1.82-1.88 (m, 2H), 2.72-2.77 (m, 2H), 3.05 (q, J=7.1 Hz, 6H), 3.22 (s,4H), 3.47 (t, J=6.8 Hz, 2H)

Compound 143. ¹H NMR (400 MHz, D₂O) δ ppm 3.09-3.18 (m, 5H), 3.60-3.66(m, 1H), 3.68-3.75 (m, 1H), 4.09-4.15 (m, 1H), 5.09 (d, J=4.1 Hz, 1H),7.57 (d, J=8.9 Hz, 2H), 8.18 (d, J=8.9 Hz, 2H).

Compound 145. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.29 (t, J=7.3 Hz, 2H),3.14-3.25 (m, 4H), 4.83 (dd, J=12.2, 4.9 Hz, 1H), 6.65 (d, J=8.1 Hz,2H), 6.93 (d, J=8.1 Hz, 2H).

Compound 153. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.88-1.01 (m, 9H), 1.01-1.31(m, 2H), 1.33-1.73 (m, 3H), 1.73-2.08 (m, 4H), 2.23-2.57 (m, 2H),2.95-3.25 (m, 4H), 6.25 (d, J=6.0 Hz, 1H).

Compound 158. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.90-0.99 (m, 15H),1.55-1.64 (m, 5H), 1.77-1.87 (m, 3H).

Compound 165. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.96 (d, J=6.4 Hz, 2H),1.01-1.17 (m, 4H), 1.47-1.60 (m, 1H), 1.60-1.84 (m, 3H), 1.86-2.10 (m,2H), 2.22-2.41 (m, 1H), 2.48-2.68 (m, 1H), 7.16 (dd, J=8.9, 2.5 Hz, 1H),7.28 (d, J=4.9 Hz, 1H), 8.04 (s, 1H), 8.28-8.50 (m, 1H).

Compound 166. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.69 (s,3H), 6.20 (dd, J=8.4, 2.5 Hz, 1H), 6.38 (d, J=2.5 Hz, 1H), 6.70 (d,J=8.4 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 10.65 (s, 1H).

Compound 167. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.42 (d, J=8.4 Hz, 1H), 7.77(dd, J=8.7, 2.2 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H).

Compound 168. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.01-7.14 (m, 1H), 7.32-7.38(m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 8.00 (s, 1H),10.07 (s, 1H).

Compound 169. ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.49-6.64 (m, 1H),6.75-6.95 (m, 1H), 7.22 (t, J=8.9 Hz, 1H), 7.65 (dd, J=8.9, 4.9 Hz, 1H).

Compound 172. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.14-1.37 (m, 3H), 1.37-1.59(m, 2H), 1.62-1.71 (m, 1H), 1.71-1.91 (m, 2H), 1.98-2.06 (m, 1H), 2.10(d, J=9.9 Hz, 1H), 7.92 (br. s, 1H).

Compound 173. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.4 Hz, 2H),0.90-1.12 (m, 2H), 1.40-1.64 (m, 2H), 1.68-1.77 (m, 1H), 1.77-1.97 (m,2H), 1.97-2.08 (m, 1H), 2.64-2.87 (m, 1H), 2.99-3.20 (m, 1H), 7.65-7.77(m, 2H), 8.29 (d, J=8.4 Hz, 1H), 9.09 (d, J=3.0 Hz, 1H), 11.05 (br. s,1H), 12.09 (br. s, 1H).

Compound 174. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.78-1.01 (m, 3H),1.07-1.31 (m, 1H), 1.36-1.60 (m, 3H), 1.62-1.75 (m, 1H), 1.75-1.94 (m,2H), 2.00 (dd, J=13.4, 3.0 Hz, 1H), 2.56-2.75 (m, 1H), 7.06 (dd, J=6.9,4.9 Hz, 1H), 7.74 (t, J=7.9 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 8.29 (d,J=3.0 Hz, 1H), 10.03-10.16 (m, 1H), 11.97 (br. s, 1H).

Compound 175. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.82-1.02 (m, 4H),1.35-1.53 (m, 1H), 1.53-1.68 (m, 2H), 1.72 (dd, J=12.6, 2.7 Hz, 1H),1.76-1.89 (m, 1H), 2.00 (d, J=13.4 Hz, 1H), 2.16 (d, J=9.9 Hz, 7H),2.94-3.17 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.38(br. s, 1H), 9.38 (d, J=4.0 Hz, 1H), 11.93 (br. s, 1H).

Compound 176. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-1.02 (m, 6H),1.41-1.65 (m, 3H), 1.77-1.96 (m, 3H), 2.01 (d, J=12.9 Hz, 1H), 3.06 (d,J=4.5 Hz, 1H), 7.08 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.77 (br.s, 1H), 9.53 (d, J=5.9 Hz, 1H), 11.98 (br. s, 1H).

Compound 177. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-1.04 (m, 4H), 1.48(d, J=2.0 Hz, 2H), 1.53-1.77 (m, 3H), 1.85 (dd, J=16.6, 13.1 Hz, 1H),1.94-2.08 (m, 1H), 3.04-3.16 (m, 1H), 6.92-7.06 (m, 3H), 7.09 (t, J=7.4Hz, 1H), 7.36 (t, J=7.9 Hz, 2H), 7.60 (d, J=8.9 Hz, 2H), 9.57 (d, J=4.0Hz, 1H), 11.98 (br. s, 1H).

Compound 178. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-1.03 (m, 4H), 1.13(d, J=12.9 Hz, 1H), 1.41-1.52 (m, 1H), 1.53-1.68 (m, 2H), 1.80-1.91 (m,1H), 1.91-2.07 (m, 2H), 2.99-3.11 (m, 1H), 4.43 (br. s, 2H), 5.09 (br.s, 1H), 7.23 (m, 2H), 7.55 (m, 2H), 9.50 (s, 1H), 11.97 (br. s, 1H).

Compound 179. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.78-0.97 (m, 4H), 1.58(d, J=12.4 Hz, 2H), 1.77-1.94 (m, 2H), 2.01 (d, J=13.4 Hz, 1H), 2.30 (s,4H), 2.93-3.12 (m, 1H), 7.28-7.41 (m, 1H), 7.46 (d, J=8.9 Hz, 1H),7.53-7.73 (m, 1H), 9.60 (d, J=6.9 Hz, 1H), 11.97 (br. s, 1H).

Compound 180. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.97 (m, 5H), 1.26(d, J=5.9 Hz, 8H), 1.59 (s, 2H), 2.00 (d, J=2.0 Hz, 3H), 3.05 (br. s,1H), 4.41-4.62 (m, 1H), 6.56 (dd, J=7.9, 2.5 Hz, 1H), 7.00-7.22 (m, 2H),9.48 (d, J=3.5 Hz, 1H), 11.95 (s, 1H).

Compound 181. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-1.02 (m, 6H),1.12-1.25 (m, 6H), 1.48 (br. s, 1H), 1.53-1.76 (m, 2H), 1.76-1.94 (m,1H), 1.94-2.09 (m, 1H), 2.97-3.10 (m, 1H), 3.13 (s, 1H), 3.17 (s, 1H),3.94 (dq, J=7.4, 7.3 Hz, 4H), 7.17 (dd, J=8.7, 2.2 Hz, 2H), 7.51 (d,J=8.4 Hz, 2H), 9.52 (d, J=3.5 Hz, 1H), 11.95 (br. s, 1H).

Compound 182. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (d, J=4.9 Hz, 3H),0.90-1.06 (m, 2H), 1.41-1.65 (m, 3H), 1.72 (d, J=10.9 Hz, 1H), 1.79-1.96(m, 2H), 2.01 (d, J=12.9 Hz, 1H), 3.06 (d, J=4.0 Hz, 1H), 5.16 (s, 2H),7.17 (d, J=7.4 Hz, 1H), 7.29-7.52 (m, 5H), 7.80 (d, J=2.0 Hz, 1H), 9.54(d, J=4.5 Hz, 1H), 11.98 (br. s, 1H).

Compound 184. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.83-1.06 (m, 6H),1.06-1.19 (m, 1H), 1.41-1.52 (m, 1H), 1.54-1.69 (m, 2H), 1.77-1.98 (m,1H), 1.98-2.05 (m, 1H), 3.07 (d, J=4.0 Hz, 1H), 4.46 (br. s, 2H), 6.96(d, J=7.4 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.46 (d, J=6.9 Hz, 1H), 7.59(br. s, 1H), 9.48-9.58 (m, 1H), 11.94 (br. s, 1H).

Compound 185. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-1.03 (m, 6H),1.18-1.34 (m, 8H), 1.34-1.51 (m, 4H), 1.53-1.75 (m, 5H), 1.76-1.90 (m,1H), 1.90-2.11 (m, 2H), 2.94-3.14 (m, 1H), 3.90 (t, J=6.7 Hz, 2H), 6.83(m, J=8.9 Hz, 2H), 7.45 (m, J=8.9 Hz, 2H), 9.38 (s, 1H), 11.95 (br. s,1H).

Compound 186. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.97 (m, 5H), 1.48(br. s, 2H), 1.51-1.67 (m, 2H), 1.79-1.96 (m, 2H), 2.02 (dd, J=13.4, 3.0Hz, 1H), 2.26 (s, 3H), 2.97-3.18 (m, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.35(ddd, J=8.2, 2.5, 2.2 Hz, 1H), 7.68-7.87 (m, 1H), 9.62 (d, J=6.4 Hz,1H), 11.98 (br. s, 1H).

Compound 187. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.85-1.09 (m, 6H), 1.33-1.45(m, 8H), 1.52 (br. s, 2H), 1.61 (d, J=11.9 Hz, 1H), 1.75 (d, J=12.4 Hz,1H), 1.91-2.08 (m, 1H), 2.18-2.37 (m, 1H), 3.36 (d, J=13.9 Hz, 1H), 4.59(ddd, J=12.2, 6.1, 5.9 Hz, 1H), 8.15 (br. s, 1H).

Compound 188. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.82-1.03 (m, 4H), 1.48(br. s, 1H), 1.52-1.76 (m, 2H), 1.81-1.96 (m, 1H), 1.97-2.09 (m, 1H),2.28 (s, 3H), 2.94-3.16 (m, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.39-7.53 (m,1H), 7.53-7.71 (m, 1H), 9.59 (d, J=6.9 Hz, 1H), 11.96 (br. s, 1H).

Compound 189. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.86-1.04 (m, 7H), 1.13-1.25(m, 5H), 1.43-1.66 (m, 4H), 1.84 (br. s, 2H), 1.87-1.99 (m, 1H),2.35-2.56 (m, 1H), 3.63-3.87 (m, 3H).

Compound 190. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.81-0.93 (m, 5H),0.95-1.05 (m, 5H), 1.34-1.58 (m, 4H), 1.69 (d, J=11.9 Hz, 3H), 1.98 (br.s, 2H), 3.26-3.37 (m, 1H), 3.37-3.44 (m, 1H), 3.54-3.68 (m, 1H), 3.87(ddd, J=6.2, 3.0, 2.7 Hz, 1H).

Compound 195. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.03-1.27 (m, 4H), 1.55(d, J=11.9 Hz, 1H), 1.59-1.73 (m, 2H), 1.73-1.94 (m, 2H), 8.13 (br. s,2H).

Compound 196. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.20 (t, J=7.9 Hz, 1H),7.51 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H),8.11 (s, 1H), 11.10 (s, 1H).

Compound 199. ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.57 (dd, J=8.7, 4.7 Hz,2H), 6.85 (t, J=8.9 Hz, 2H).

Compound 201. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.80 (br. s, 2H), 7.92(br. s, 1H), 7.98 (br. s, 1H).

Compound 202. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.68 (s,4H), 6.23 (dd, J=8.4, 2.5 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 6.71 (d,J=8.4 Hz, 1H), 10.65 (br. s, 1H).

Compound 211. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.31 (d, J=5.9 Hz, 6H),4.48-4.67 (m, 1H), 7.50 (s, 1H).

Compound 216. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.96 (m, 8H), 1.78(dd, J=13.4, 6.9 Hz, 1H), 2.52 (d, J=7.4 Hz, 1H), 2.93 (t, J=6.2 Hz,1H), 8.12 (br. s, 2H).

Compound 218. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.61 (d, J=8.4 Hz, 1H),7.81 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 11.08 (s, 1H).

Compound 222. ¹H NMR (300 MHz, DMSO-d6) δ ppm 6.65 (d, J=8.8 Hz, 2H),6.74-6.91 (m, 3H), 6.94-7.18 (m, 3H), 7.30 (t, J=8.0 Hz, 1H), 7.37 (t,J=7.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H).

Compound 223. ¹H NMR (300 MHz, DMSO-d6) δ ppm 4.46 (s, 2H), 7.29 (m,J=8.1 Hz, 2H), 7.55 (m, J=8.6 Hz, 2H), 10.64 (s, 1H).

Compound 223Na. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.44 (s, 2H), 7.23 (m,J=8.4 Hz, 2H), 7.58 (m, J=8.4 Hz, 2H), 10.34 (s, 1H).

Compound 226. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.21 (t, J=6.9 Hz, 6H),3.31 (s, 2H), 3.36 (s, 2H), 4.00 (qd, J=7.3, 7.2 Hz, 4H), 7.34-7.40 (m,2H), 7.44 (d, J=6.4 Hz, 2H).

Compound 227. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.00 (s, 2H), 6.55 (dd,J=8.7, 2.7 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.36(t, J=7.4 Hz, 2H), 7.38-7.47 (m, 2H).

Compound 232. ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H), 6.41 (d,J=7.5 Hz, 1H), 6.51 (br. s, 1H), 6.99 (d, J=8.3 Hz, 1H).

Compound 236. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.65-2.84 (m, 2H),3.29-3.40 (m, 2H), 3.42-3.54 (m, 2H), 7.13-7.23 (m, 1H), 7.30-7.37 (m,2H), 8.07 (br. s, 2H), 8.17 (d, J=8.9 Hz, 1H).

Compound 237. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.01-3.13 (m, 1H), 3.45(d, J=11.4 Hz, 2H), 3.94 (t, J=10.9 Hz, 1H), 4.28 (td, J=9.6, 4.0 Hz,1H), 5.14 (d, J=9.4 Hz, 1H), 7.67-7.76 (m, 3H), 8.27 (d, J=8.4 Hz, 2H).

Compound 238. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.90 (s, 1H), 3.07 (dd,J=11.4, 4.0 Hz, 1H), 3.18-3.30 (m, 1H), 3.47 (d, J=3.5 Hz, 1H), 3.95 (t,J=10.9 Hz, 1H), 4.22-4.34 (m, 1H), 5.14 (d, J=9.4 Hz, 1H), 7.68-7.76 (m,2H), 8.27 (d, J=8.4 Hz, 2H).

Compound 239. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.20 (s, 2H), 7.24 (d,J=8.8 Hz, 1H), 7.30-7.37 (m, 1H), 7.37-7.45 (m, 3H), 7.45-7.53 (m, 2H),7.78 (d, J=2.0 Hz, 1H), 10.74 (s, 1H).

Compound 243. ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (br. s, 8H), 2.48 (d,J=2.5 Hz, 4H), 5.15 (s, 2H), 7.16 (d, J=9.1 Hz, 1H), 7.27-7.58 (m, 6H),7.82 (d, J=1.9 Hz, 1H), 9.87 (s, 1H), 11.98 (br. s, 1H).

Compound 246. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.54-1.70 (m, 8H), 2.47(s, 2H), 2.55 (s, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8, 2.4 Hz,1H), 8.19 (d, J=2.4 Hz, 1H), 10.28 (s, 1H), 11.99 (br. s, 1H).

Compound 251. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.20 (s, 3H), 7.25 (d,J=9.4 Hz, 1H), 7.33 (t,

J=7.2 Hz, 1H), 7.40 (t, J=7.4 Hz, 3H), 7.45-7.47 (m, 2H), 7.80 (d, J=2.5Hz, 1H), 10.84 (s, 1H).

Compound 252. ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.96 (d, J=8.4 Hz, 1H),7.26 (dd, J=8.9, 2.5 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 10.11 (br. s, 1H),10.62 (s, 1H).

Compound 253. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.20 (s, 2H), 7.25 (d,J=9.4 Hz, 1H), 7.34 (d, J=6.9 Hz, 1H), 7.40 (t, J=7.4 Hz, 3H), 7.43-7.49(m, 2H), 7.80 (d, J=2.5 Hz, 1H), 10.84 (s, 1H).

Compound 254. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.45 (s, 2H), 7.22 (m,J=8.4 Hz, 2H), 7.53 (m, J=8.4 Hz, 2H), 10.82 (br. s, 1H).

Compound 255. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.42 (ddd, J=16.2, 8.0,7.9 Hz, 2H), 7.83 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 11.36 (br. s, 1H).

Compound 257. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (s, 3H), 7.36-7.51(m, 2H), 7.63 (d, J=2.5 Hz, 1H), 10.87 (s, 1H).

Compound 258. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.68-7.78 (m, 1H), 7.83(dd, J=8.7, 2.2 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 11.32 (s, 1H).

Compound 259. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.99-3.04 (m, 4H), 7.00(d, J=9.4 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.54(s, 1H), 9.86 (s, 1H), 10.87 (s, 1H).

Compound 261. ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.93 (d, J=6.4 Hz, 1H),7.23 (br. s, 1H), 7.73 (br. s, 1H), 10.80 (br. s, 1H).

Compound 262. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.49 (s, 2H), 7.06 (d,J=7.4 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.70 (s,1H), 10.90 (s, 1H).

Compound 263. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (t, J=6.9 Hz, 6H),3.18 (s, 1H), 3.22 (s, 1H), 3.96 (quin, J=7.4 Hz, 4H), 7.26 (dd, J=8.4,2.5 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 10.77 (s, 1H).

Compound 264. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.74 (d, J=2.5 Hz, 7H),6.94 (d, J=8.4 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H),10.63 (s, 1H).

Compound 265. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.81-0.91 (m, 3H),1.15-1.36 (m, 9H), 1.36-1.51 (m, 2H), 1.60-1.76 (m, 2H), 3.90 (t, J=6.7Hz, 2H), 6.83 (m, J=8.9 Hz, 2H), 7.53 (m, J=8.9 Hz, 2H), 10.47 (br. s,1H).

Compound 267. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.25 (d, J=6.9 Hz, 1H),4.32-4.44 (m, 1H), 4.49 (dd, J=8.2, 4.2 Hz, 1H), 5.22 (br. s, 1H), 7.73(d, J=8.9 Hz, 2H), 8.07 (d, J=8.9 Hz, 2H), 8.49 (d, J=8.9 Hz, 1H).

Compound 268. ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.69-6.79 (m, 1H), 7.05(d, J=7.9 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.23-7.32 (m, 2H), 7.40 (t,J=8.2 Hz, 2H), 10.92 (br. s, 1H).

Compound 269. ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.76-7.88 (m, 2H),7.88-8.08 (m, 2H).

Compound 270. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.82-0.93 (m, 3H),1.19-1.37 (m, 8H), 1.37-1.52 (m, 2H), 1.59-1.80 (m, 2H), 3.94 (t, J=6.4Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 7.47-7.68 (m, 5H), 7.87 (d, J=7.9 Hz,1H), 10.19 (s, 1H), 13.02 (br. s, 1H).

Compound 271. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.74-0.95 (m, 3H),1.18-1.35 (m, 9H), 1.35-1.54 (m, 2H), 1.60-1.82 (m, 2H), 3.92 (t, J=6.4Hz, 2H), 6.89 (m, J=8.9 Hz, 2H), 7.51 (m, J=8.9 Hz, 2H), 10.63 (s, 1H).

Compound 272. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.20 (s, 2H), 7.22 (d,J=8.9 Hz, 1H), 7.31-7.38 (m, 1H), 7.42 (t, J=7.7 Hz, 3H), 7.46-7.54 (m,4H), 7.54-7.65 (m, 3H), 7.84 (d, J=7.4 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H).

Compound 273. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.85 (d, J=8.9 Hz, 2H),8.11 (d, J=8.4 Hz, 2H), 11.40 (br. s, 1H).

Compound 274. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.96 (m, 3H),1.20-1.35 (m, 9H), 1.35-1.52 (m, 2H), 1.59-1.80 (m, 2H), 3.90 (t, J=6.4Hz, 2H), 6.82 (m, J=8.9 Hz, 2H), 7.54 (m, J=8.9 Hz, 2H), 10.40 (br. s,1H). ¹³C NMR (126 MHz, DMSO-d6) δ ppm 14.5, 22.5, 26.0, 29.2, 29.3,31.8, 68.3, 115.7, 123.4, 126.4, 127.9, 135.5, 155.4, 157.2.

Compound 275. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.1 Hz, 3H),1.23-1.46 (m, 4H), 1.62-1.82 (m, 2H), 3.95 (t, J=6.5 Hz, 2H), 6.92 (d,J=9.2 Hz, 2H), 7.49-7.59 (m, 2H), 7.59-7.71 (m, 3H), 7.90 (d, J=7.8 Hz,1H), 10.22 (s, 1H).

Compound 277-1. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.18 (s, 2H), 6.98-7.06(m, 1H), 7.17-7.24 (m, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.34-7.40 (m, 2H),7.42-7.48 (m, 2H).

Compound 277-2. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.26 (s, 2H), 7.10 (dd,J=8.8, 2.6 Hz, 1H), 7.27 (d, J=2.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.40-7.46(m, 2H), 7.46-7.53 (m, 2H).

Compound 278. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.16 (br. s, 2H), 7.12 (d,J=8.6 Hz, 1H), 7.33 (d, J=6.8 Hz, 2H), 7.36-7.42 (m, 3H), 7.45 (d, J=7.0Hz, 2H), 7.91 (br. s, 1H), 10.71 (br. s, 1H).

Compound 279-2. ¹H NMR (500 MHz, METHANOL-d4) δ ppm 0.94 (t, J=6.7 Hz,3H), 1.26-1.45 (m, 8H), 1.50 (d, J=7.6 Hz, 2H), 1.73-1.86 (m, 2H), 3.98(t, J=6.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.46-7.70 (m, 5H), 7.87 (d,J=6.8 Hz, 1H).

Compound 280-2. ¹H NMR (500 MHz, METHANOL-d4) δ ppm 0.89 (t, J=6.6 Hz,3H), 1.24-1.38 (m, 9H), 1.44 (d, J=7.8 Hz, 3H), 1.68-1.79 (m, 2H), 3.92(t, J=6.4 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H).

Compound 281. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.92 (m, 3H),1.22-1.35 (m, 8H), 1.41 (d, J=7.6 Hz, 2H), 1.65-1.77 (m, 2H), 3.99 (t,J=6.5 Hz, 2H), 7.06 (m, 4H).

Compound 282. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.78-0.99 (m, 3H), 1.23-1.38(m, 10H), 1.42 (dd, J=14.6, 6.8 Hz, 2H), 1.68-1.89 (m, 3H), 3.42 (s,3H), 3.84-3.95 (m, 2H), 6.74 (m, J=9.0 Hz, 2H), 7.29 (m, 2H).

Compound 288. ¹H NMR (300 MHz, acetone-d6) δ ppm 0.78-0.99 (m, 3H), 1.27(br. s, 23H), 1.40-1.61 (m, 2H), 1.68-1.88 (m, 2H), 1.96-2.13 (m, 2H),3.96 (t, J=6.6 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.44-7.77 (m, 4H), 7.92(d, J=8.1 Hz, 1H).

Compound 289. ¹H NMR (300 MHz, acetone-d6) δ ppm 0.72-0.98 (m, 2H), 1.27(br. s, 24H), 1.41 (br. s, 2H), 1.42-1.63 (m, 2H), 1.64-1.93 (m, 2H),1.98-2.21 (m, 1H), 3.96 (t, J=6.6 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.58(d, J=9.0 Hz, 2H).

Compound 290. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.75-0.92 (m, 3H),1.08-1.47 (m, 25H), 1.66 (br. s, 2H), 3.36 (br. s, 2H), 3.85 (br. s,2H), 6.75 (m, J=7.9 Hz, 2H), 7.51 (m, J=7.9 Hz, 2H), 10.54 (br. s, 1H).

Compound 291. ¹H NMR (300 MHz, acetone) δ ppm 0.77-0.95 (m, 3H), 1.27(br. s, 25H), 1.69-1.84 (m, 2H), 1.96-2.10 (m, 3H), 3.97 (t, J=6.6 Hz,2H), 6.84-6.96 (m, 2H), 7.50-7.66 (m, 2H).

Compound 293. ¹H NMR (300 MHz, acetone) δ ppm 0.80-0.99 (m, 3H),1.21-1.45 (m, 8H), 1.45-1.63 (m, 2H), 1.79-1.96 (m, 2H), 4.25 (t, J=6.6Hz, 2H), 7.30 (d, J=9.0 Hz, 1H), 8.12-8.28 (m, 1H).

Compound 295. ¹H NMR (300 MHz, acetone) δ ppm 3.23 (s, 3H), 5.10 (s,2H), 6.73-6.94 (m, 3H), 7.12 (d, J=9.0 Hz, 2H), 7.21-7.45 (m, 4H).

Compound 297. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.83-0.98 (m, 3H), 1.24-1.43(m, 8H), 1.43-1.56 (m, 2H), 1.72-1.90 (m, 2H), 3.30 (s, 3H), 3.96 (t,J=6.6 Hz, 2H), 5.18 (br. s, 2H), 6.80-7.00 (m, 2H), 7.16 (br. s, 2H),7.33 (d, J=13.8 Hz, 4H).

Compound 298. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.75-0.91 (m, 3H), 1.26 (d,J=2.4 Hz, 10H), 1.59-1.83 (m, 2H), 3.82 (t, J=6.3 Hz, 2H), 6.75 (m,J=8.5 Hz, 2H), 7.34 (m, J=8.5 Hz, 2H), 10.19 (br. s, 1H).

Compound 299. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.84-0.95 (m, 3H), 1.28-1.37(m, 8H), 1.44-1.53 (m, 2H), 1.73-1.85 (m, 2H), 3.47 (br. s, 2H), 3.93(t, J=6.6 Hz, 2H), 6.53 (dd, J=8.6, 2.8 Hz, 1H), 6.71-6.82 (m, 2H).

Compound 300. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.84-0.89 (m, 3H),1.22-1.37 (m, 8H), 1.38-1.47 (m, 2H), 1.67-1.76 (m, 2H), 4.01 (t, J=6.4Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 7.49 (dd, J=8.9, 2.5 Hz, 1H), 7.51-7.55(m, 1H), 7.57 (td, J=7.6, 1.2 Hz, 1H), 7.63-7.68 (m, 1H), 7.79-7.96 (m,2H), 10.32 (s, 1H).

Compound 301. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.92 (m, 3H),1.19-1.38 (m, 8H), 1.38-1.50 (m, 2H), 1.63-1.81 (m, 2H), 4.03 (t, J=6.4Hz, 2H), 7.15 (d, J=9.0 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.78 (d,J=2.4 Hz, 1H), 10.82 (s, 1H).

Compound 302. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (td, J=6.9, 1.7 Hz,3H), 1.16-1.37 (m, 8H), 1.37-1.52 (m, 2H), 1.63-1.84 (m, 3H), 4.03 (t,J=6.4 Hz, 2H), 7.15 (d, J=9.0 Hz, 1H), 7.40 (dd, J=8.8, 2.6 Hz, 1H),7.76 (d, J=2.4 Hz, 1H), 10.80 (s, 1H).

Compound 303. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.78-0.92 (m, 3H),1.17-1.36 (m, 8H), 1.36-1.52 (m, 2H), 1.62-1.79 (m, 3H), 4.02 (t, J=6.4Hz, 2H), 7.15 (d, J=9.0 Hz, 1H), 7.39 (dd, J=9.0, 2.4 Hz, 1H), 7.75 (d,J=2.4 Hz, 1H), 10.71 (s, 1H).

Compound 304. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.78-0.88 (m, 4H),1.21-1.28 (m, 9H), 1.31 (d, J=7.2 Hz, 3H), 1.57-1.64 (m, 2H), 3.80 (t,J=6.5 Hz, 2H), 6.70 (d, J=8.8 Hz, 2H), 7.08-7.19 (m, 3H), 7.22-7.31 (m,1H), 7.35 (dd, J=7.6, 1.2 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H).

Compound 305. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.95 (m, 3H),1.18-1.28 (m, 10H), 1.28-1.39 (m, 3H), 1.58-1.70 (m, 2H), 3.86 (t, J=6.5Hz, 2H), 6.81 (m, 2H), 7.25 (m, 2H).

Compound 306. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.86-0.97 (m, 3H), 1.22-1.38(m, 11H), 1.38-1.51 (m, 3H), 1.68-1.84 (m, 2H), 3.82-3.95 (m, 2H), 6.72(d, J=8.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H).

Compound 307. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.91 (q, J=6.7 Hz, 3H),1.23-1.39 (m, 9H), 1.39-1.52 (m, 2H), 1.69-1.85 (m, 2H), 2.98 (s, 1H),3.91 (t, J=6.6 Hz, 2H), 6.74 (t, J=9.5 Hz, 2H), 7.20 (d, J=8.6 Hz, 1H),7.27-7.35 (m, 1H), 7.43 (d, 1H).

Compound 308. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.92 (dd, J=4.7, 1.7 Hz,3H), 1.23-1.42 (m, 9H), 1.46 (d, J=6.0 Hz, 2H), 1.67-1.85 (m, 2H), 2.82(d, J=5.6 Hz, 3H), 3.91 (td, J=6.6, 2.0 Hz, 2H), 6.53-6.67 (m, 2H),6.75-6.90 (m, 2H).

Compound 310. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.79-0.95 (m, 3H), 1.17-1.40(m, 12H), 1.41-1.60 (m, 2H), 1.76-1.93 (m, 2H), 4.04 (t, J=6.5 Hz, 2H),6.82-6.99 (m, 2H), 8.09-8.25 (m, 2H).

Compound 311. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.81-0.97 (m, 3H), 1.23-1.38(m, 13H), 1.38-1.50 (m, 2H), 1.67-1.85 (m, 2H), 3.88 (t, J=6.6 Hz, 2H),6.61-6.71 (m, 2H), 6.71-6.80 (m, 2H).

Compound 312. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.80-0.95 (m, 3H), 1.21-1.43(m, 13H), 1.43-1.62 (m, 2H), 1.77-2.01 (m, 2H), 4.12 (t, J=6.6 Hz, 2H),6.96 (d, J=9.0 Hz, 1H), 8.13 (dd, J=9.0, 2.6 Hz, 1H).

Compound 314. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.82-0.99 (m, 3H), 1.20-1.38(m, 13H), 1.45 (d, J=7.7 Hz, 3H), 1.70-1.89 (m, 2H), 3.29 (s, 3H), 3.95(t, J=6.6 Hz, 2H), 5.16 (s, 2H), 6.87 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.1Hz, 2H), 7.31 (br. s, 3H).

Compound 315. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.79-1.01 (m, 3H), 1.29 (br.s, 11H), 1.35-1.53 (m, 4H), 1.68-1.87 (m, 2H), 2.81 (s, 3H), 3.90 (t,J=6.4 Hz, 2H), 6.58 (m, J=9.0 Hz, 2H), 6.81 (m, 2H).

Compound 316. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.73-0.89 (m, 3H),1.10-1.44 (m, 17H), 1.52-1.74 (m, 2H), 3.79 (t, J=6.2 Hz, 2H), 3.92 (t,J=6.4 Hz, 1H), 6.61-6.77 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 7.41 (d, J=8.6Hz, 1H).

Compound 317. ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.1 Hz, 2H),7.48-7.59 (m, 2H), 7.59-7.67 (m, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.88 (d,J=7.3 Hz, 1H), 10.47 (s, 1H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 121.3,127.2, 127.9, 128.8, 129.8, 130.0, 132.0, 138.6, 138.8, 167.6, 167.8.

Compound 318. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.76-0.93 (m, 6H), 1.23(br. s, 16H), 1.52-1.72 (m, 4H), 3.80 (t, J=6.4 Hz, 2H), 6.69 (d, J=8.6Hz, 2H), 7.07-7.20 (m, 2H), 7.20-7.42 (m, 1H).

Compound 319. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.82 (t, J=6.7 Hz, 3H),1.17-1.29 (m, 12H), 1.32 (d, J=8.0 Hz, 2H), 1.57-1.66 (m, 2H), 3.30 (s,3H), 3.85 (t, J=6.4 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.23 (d, J=8.6 Hz,2H).

Compound 324. ¹H NMR (600 MHz, CDCl₃) δ ppm 0.84-0.95 (m, 3H), 1.32-1.44(m, 2H), 1.65 (dd, J=14.9, 7.1 Hz, 2H), 3.89 (br. s, 1H), 4.14-4.27 (m,2H), 7.39-7.51 (m, 3H), 7.79-7.93 (m, 2H).

Compound 325. ¹H NMR (500 MHz, Acetone) δ ppm 1.00 (t, J=7.4 Hz, 3H),1.44-1.61 (m, 2H), 1.68-1.87 (m, 2H), 4.31 (t, J=6.6 Hz, 3H), 7.11 (td,J=7.6, 1.1 Hz, 1H), 7.62 (ddd, J=8.7, 7.2, 1.6 Hz, 1H), 7.73-7.86 (m,2H), 7.96-8.05 (m, 2H), 8.11 (dd, J=7.9, 1.7 Hz, 1H), 8.65 (d, J=8.8 Hz,1H), 9.48 (br. s, 1H), 10.69 (br. s, 1H).

Compound 326. ¹H NMR (600 MHz, CDCl₃) δ ppm 0.95 (t, J=7.3 Hz, 3H),1.36-1.51 (m, 2H), 1.60-1.77 (m, 2H), 3.27 (s, 3H), 4.24 (t, J=6.6 Hz,2H), 6.24 (br. s, 1H), 7.21-7.36 (m, 2H), 7.41 (d, J=7.3 Hz, 1H), 7.53(t, J=7.3 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 8.12(d, J=7.3 Hz, 1H).

Compound 329. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (br. s, 3H), 1.25(br. s, 13H), 1.65 (br. s, 2H), 3.83 (br. s, 2H), 6.60 (d, J=7.0 Hz,3H), 6.74 (br. s, 3H)

Compound 331. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.78-1.07 (m, 3H), 1.28-1.55(m, 2H), 1.58-1.80 (m, 2H), 4.13-4.34 (m, 2H), 7.36-7.58 (m, 3H), 7.65(d, J=7.7 Hz, 2H), 7.90 (d, J=7.7 Hz, 3H).

Compound 332. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.79-1.05 (m, 3H), 1.26-1.59(m, 2H), 1.59-1.86 (m, 2H), 4.15-4.35 (m, 2H), 7.63 (d, J=8.6 Hz, 2H),7.81-8.10 (m, 2H).

Compound 333. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.80-1.00 (m, 3H), 1.31-1.52(m, 2H), 1.60-1.77 (m, 2H), 3.80 (s, 2H), 4.12-4.34 (m, 2H), 7.61 (m,J=8.6 Hz, 2H), 7.91 (m, J=8.6 Hz, 2H).

Compound 334. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.89 (t, J=7.4 Hz, 3H),1.30-1.46 (m, 2H), 1.59-1.73 (m, 2H), 3.95 (s, 2H), 4.21 (t, J=6.7 Hz,2H), 7.59 (m, J=9.1 Hz, 2H), 7.89 (m, J=8.6 Hz, 2H).

Compound 335. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.79 (dd, J=4.8, 2.6 Hz,2H), 3.36 (dt, J=4.1, 2.9 Hz, 1H), 4.43 (dd, J=11.3, 2.5 Hz, 2H), 6.98(d, J=9.1 Hz, 1H), 8.07 (dd, J=9.1, 2.8 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H).

Compound 336. ¹H NMR (600 MHz, CDCl₃) δ ppm 0.96 (t, J=7.3 Hz, 3H),1.39-1.55 (m, 2H), 1.63-1.78 (m, 2H), 3.35 (s, 2H), 4.25 (t, J=6.6 Hz,4H), 6.65 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H).

Compound 337. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.70-0.93 (m, 7H), 1.29-1.69(m, 7H), 1.71-1.91 (m, 2H), 2.02-2.21 (m, 1H), 2.35-2.57 (m, 1H),3.03-3.18 (m, 1H), 3.97 (br. s, 2H), 4.07-4.24 (m, 2H), 7.51 (d, J=7.2Hz, 2H), 7.85 (d, J=8.1 Hz, 2H).

Compound 338. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.77-0.94 (m, 3H), 1.27 (d,J=7.7 Hz, 8H), 1.33-1.50 (m, 4H), 1.67-1.86 (m, 2H), 4.39 (t, J=6.7 Hz,2H), 6.78 (d, J=9.1 Hz, 1H), 8.31 (dd, J=9.1, 2.9 Hz, 1H), 9.03 (d,J=2.9 Hz, 1H).

Compound 339. ¹H NMR (300 MHz, CDCl₃) δ ppm 5.53 (s, 2H), 6.92 (d, J=9.1Hz, 1H), 7.34-7.56 (m, 5H), 8.40 (dd, J=9.1, 2.8 Hz, 1H), 9.13 (d, J=2.5Hz, 1H).

Compound 340. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.90 (t, J=7.4 Hz, 3H),1.26-1.46 (m, 2H), 1.48-1.67 (m, 2H), 3.50 (t, J=6.0 Hz, 3H), 3.64 (d,J=4.3 Hz, 3H), 4.13-4.28 (m, 4H), 7.03 (d, J=9.6 Hz, 1H), 8.14 (dd,J=9.1, 2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H).

Compound 341. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.14-0.29 (m, 2H), 0.51-0.63(m, 2H), 1.00-1.17 (m, 1H), 3.39 (d, J=7.2 Hz, 3H), 3.65-3.77 (m, 3H),4.19-4.34 (m, 4H), 7.07 (d, J=9.0 Hz, 1H), 8.18 (dd, J=9.3, 2.8 Hz, 1H),8.32 (d, J=2.8 Hz, 1H).

Compound 342. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.75-0.92 (m, 3H), 1.27 (br.s, 8H), 1.32-1.48 (m, 4H), 1.58-1.86 (m, 3H), 3.78 (br. s, 3H),4.06-4.27 (m, 2H), 6.50-6.66 (m, 1H), 7.07 (dd, J=8.9, 3.1 Hz, 1H), 7.69(d, J=2.9 Hz, 1H).

Compound 343. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.78-0.92 (m, 2H), 1.27(d, J=3.3 Hz, 9H), 1.59-1.85 (m, 2H), 4.21 (t, J=6.8 Hz, 2H), 6.80 (d,J=8.8 Hz, 1H), 7.49-7.78 (m, 3H), 7.81-8.13 (m, 2H), 8.41 (d, J=2.5 Hz,1H), 10.32 (s, 1H), 13.00 (br. s, 1H).

Compound 344. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.75-0.98 (m, 3H), 1.26(d, J=3.6 Hz, 10H), 1.54-1.87 (m, 2H), 4.21 (t, J=6.6 Hz, 3H), 6.83 (d,J=8.8 Hz, 1H), 7.91 (dd, J=8.8, 2.8 Hz, 1H), 8.35 (d, J=2.8 Hz, 1H),10.83 (s, 1H).

Compound 345. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.72-0.87 (m, 3H), 1.17-1.32(m, 9H), 1.36 (d, J=8.3 Hz, 2H), 1.61-1.76 (m, 2H), 4.02 (s, 3H), 4.14(t, J=6.6 Hz, 2H), 6.69 (d, J=9.1 Hz, 1H), 7.92 (dd, J=9.0, 2.6 Hz, 1H),8.15 (d, J=2.5 Hz, 1H).

Compound 346. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.74-0.93 (m, 3H), 1.26(d, J=3.6 Hz, 11H), 1.56-1.81 (m, 2H), 4.21 (t, J=6.6 Hz, 2H), 6.83 (d,J=8.8 Hz, 1H), 7.88 (dd, J=8.8, 2.8 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H),10.73 (s, 1H).

Compound 347. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.87-1.00 (m, 3H), 1.28-1.46(m, 2H), 1.48-1.66 (m, 2H), 3.50 (t, J=6.2 Hz, 3H), 3.58-3.66 (m, 2H),3.95-4.05 (m, 2H), 4.15 (t, J=5.3 Hz, 1H), 6.58 (dd, J=8.6, 2.9 Hz, 1H),6.73-6.88 (m, 2H).

Compound 348. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.72-0.93 (m, 3H), 1.21-1.39(m, 2H), 1.39-1.59 (m, 2H), 3.42 (br. s, 2H), 3.49 (td, J=6.3, 2.1 Hz,2H), 3.53-3.71 (m, 1H), 3.77 (br. s, 1H), 4.01 (br. s, 1H), 6.47 (br. s,1H), 7.12 (br. s, 1H), 7.19-7.38 (m, 2H), 7.46 (dd, J=2.5, 1.1 Hz, 2H).

Compound 349. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.3 Hz, 3H),1.20-1.39 (m, 2H), 1.39-1.59 (m, 2H), 3.32-3.54 (m, 6H), 3.84-4.10 (m,4H), 7.17 (d, J=8.8 Hz, 1H), 7.42 (dd, J=9.0, 2.6 Hz, 1H), 7.78 (d,J=2.5 Hz, 1H), 10.83 (s, 1H).

Compound 350. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.3 Hz, 3H),1.22-1.36 (m, 2H), 1.41-1.52 (m, 2H), 3.38-3.52 (m, 5H), 3.90-4.05 (m,4H), 7.17 (d, J=9.1 Hz, 1H), 7.40 (dd, J=8.8, 2.5 Hz, 1H), 10.81 (s,1H).

Compound 351. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.2 Hz, 3H),1.22-1.36 (m, 2H), 1.40-1.53 (m, 2H), 3.36-3.52 (m, 6H), 3.89-4.04 (m,4H), 7.17 (d, J=8.8 Hz, 1H), 7.34-7.44 (m, 1H).

Compound 352. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.19-0.25 (m, 3H), 0.55(ddd, J=8.0, 6.1, 4.3 Hz, 3H), 1.04-1.11 (m, 1H), 3.34-3.38 (m, 3H),3.63-3.70 (m, 3H), 3.99-4.06 (m, 3H), 4.18 (t, J=5.4 Hz, 1H), 6.55 (dd,J=8.8, 2.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H).

Compound 355. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.06-0.19 (m, 3H),0.36-0.48 (m, 3H), 0.91-1.05 (m, 1H), 3.38 (dd, J=13.9, 6.8 Hz, 2H),3.42-3.57 (m, J=15.1, 9.9, 4.9, 4.9 Hz, 3H), 3.87-4.01 (m, 3H), 7.08 (d,J=9.1 Hz, 1H), 7.39 (dd, J=9.1, 2.5 Hz, 1H), 7.79-7.85 (m, 1H)

Compound 357. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (s, 2H), 1.25 (s,7H), 1.36 (s, 3H), 1.69 (d, J=6.2 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H),7.40-7.53 (m, 2H), 7.57 (s, 3H), 7.79-7.92 (m, 1H)

Compound 358. ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.77-0.96 (m, 3H), 1.27(br. s, 9H), 1.40 (br. s, 2H), 1.56-1.91 (m, 2H), 4.30 (br. s, 3H), 7.24(d, J=9.1 Hz, 1H), 7.34-7.60 (m, 1H)

Compound 359. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.94 (m, 3H),1.17-1.36 (m, 9H), 1.36-1.48 (m, 2H), 1.62-1.81 (m, 2H), 4.19 (t, J=6.6Hz, 2H), 7.25 (d, J=9.2 Hz, 1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 8.65 (d,J=2.4 Hz, 1H), 11.13 (s, 1H)

Compound 360. ¹H NMR (600 MHz, DMSO-d6) δ ppm 0.78-0.92 (m, 3H),1.16-1.35 (m, 8H), 1.35-1.47 (m, 2H), 1.66-1.83 (m, 2H), 4.17 (t, J=6.5Hz, 1H), 4.22-4.34 (m, 1H), 7.31-7.42 (m, 1H).

Compound 361. ¹H NMR (300 MHz, CDCl₃) δ ppm 3.50 (s, 2H), 5.33 (s, 2H),6.28 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 7.31-7.45 (m, 3H),7.45-7.54 (m, 2H).

Compound 362. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.34 (s, 2H), 6.47 (d,J=8.2 Hz, 1H), 7.29-7.37 (m, 1H), 7.37-7.48 (m, 3H), 7.48-7.60 (m, 2H),7.60-7.70 (m, 1H), 7.84 (d, J=7.4 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 9.48(s, 1H).

Compound 363. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.28 (s, 2H), 6.36 (d, J=8.5Hz, 1H), 7.23-7.29 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.42 (m, 2H), 8.38(d, J=8.5 Hz, 1H).

Compound 364. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.34 (s, 2H), 6.48 (d,J=8.5 Hz, 1H), 7.28-7.49 (m, 5H), 8.03 (d, J=8.5 Hz, 1H), 10.04 (s, 1H).

Compound 365. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.28 (s, 2H), 6.34 (d, J=8.3Hz, 1H), 7.28-7.48 (m, 6H), 8.12 (s, 1H), 8.30 (d, J=8.37 Hz, 1H).

Compound 366. ¹H NMR (300 MHz, CDCl₃) δ ppm 3.88 (s, 6H), 7.49-7.61 (m,4H), 7.63-7.71 (m, 2H), 7.82-7.91 (m, 2H), 10.56 (s, 2H).

Compound 368. ¹H NMR (500 MHz, DMSO-d6) δ ppm 4.14 (s, 2H), 7.27 (s,3H), 7.49-7.57 (m, 2H), 7.69 (d, J=7.7 Hz, 2H), 7.86-7.93 (m, 3H).

Compound 370. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.78 (d, J=6.3 Hz, 3H), 5.50(d, J=6.3 Hz, 1H), 6.84-6.87 (m, 1H), 7.29-7.35 (m, 1H), 7.39 (d, J=4.3Hz, 4H), 7.98 (dd, J=9.1, 2.7 Hz, 1H), 8.29 (d, J=2.7 Hz, 1H).

Compound 371. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.43 (s, 3H), 5.26 (s, 2H),7.11 (d, J=9.1 Hz, 1H), 7.25-7.29 (m, 2H), 7.32 (d, J=6.7 Hz, 1H), 7.46(d, J=7.1 Hz, 1H), 8.18 (ddd, J=9.0, 2.6, 1.00 Hz, 1H), 8.34 (dd, J=2.5,0.8 Hz, 1H).

Compound 372. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.49 (s, 2H), 7.49 (d,J=9.1 Hz, 1H), 7.66-7.79 (m, 2H), 7.79-7.84 (m, 1H), 7.89 (s, 1H), 8.27(dd, J=9.1, 2.7 Hz, 1H), 8.32-8.36 (m, 1H). ¹³C NMR (75 MHz, DMSO-d6) δppm 70.1, 113.8, 122.1, 124.1, 124.1, 124.6, 125.0, 125.4, 129.8, 131.6,137.1, 141.0, 158.6.

Compound 375. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.27 (s, 2H), 7.04 (d, J=9.1Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.35 (s, 1H), 7.38-7.43 (m, 1H), 7.46(t, J=7.7 Hz, 1H), 8.14 (dd, J=8.9, 2.5 Hz, 1H), 8.31 (d, J=2.5 Hz, 1H).

Compound 377. ¹H NMR (600 MHz, DMSO-d6) δ ppm 2.34 (s, 3H), 4.98 (s,3H), 6.51 (dd, J=8.5, 2.6 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.97 (d,J=8.7 Hz, 1H), 7.18-7.25 (m, 3H), 7.41 (d, J=7.3 Hz, 1H).

Compound 378. ¹H NMR (500 MHz, CDCl₃) δ ppm 3.48 (s, 2H), 5.06 (s, 2H),6.50 (dd, J=8.7, 2.7 Hz, 1H), 6.72-6.81 (m, 2H), 7.47-7.51 (m, 1H), 7.58(d, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.74 (s, 1H). ¹³C NMR (126MHz, CDCl₃) δ ppm 71.6, 114.3, 117.1, 117.1, 123.1, 124.0, 124.0, 124.0,124.1, 124.5, 124.7, 124.7, 124.7, 124.8, 125.3, 128.9, 129.1, 130.6,130.9, 138.2, 141.9, 146.7.

Compound 379. ¹H NMR (600 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.3 Hz, 3H),5.58 (d, J=6.8 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 7.27 (s, 1H), 7.33-7.37(m, 3H), 7.42 (d, J=7.3 Hz, 2H), 7.51 (d, J=7.3 Hz, 1H), 7.57 (d, J=6.3Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.85-7.88 (m, 2H), 10.28 (s, 1H).

Compound 380. ¹H NMR (600 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.3 Hz, 3H),5.59 (d, J=6.3 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 7.28 (td, J=5.7, 2.2 Hz,2H), 7.36 (t, J=7.5 Hz, 2H), 7.41 (d, J=7.3 Hz, 2H), 7.78 (d, J=2.4 Hz,1H), 10.79 (s, 1H).

Compound 381. ¹H NMR (600 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.3 Hz, 3H),5.59 (d, J=6.3 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 7.23-7.30 (m, 2H),7.32-7.39 (m, 3H), 7.41 (d, J=7.3 Hz, 2H), 7.77 (d, J=2.4 Hz, 1H), 10.79(s, 1H).

Compound 382. ¹H NMR (600 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.3 Hz, 3H),5.59 (d, J=6.3 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 7.23-7.28 (m, 2H),7.33-7.38 (m, 3H), 7.41 (d, J=7.3 Hz, 2H), 7.76 (d, J=2.4 Hz, 1H), 10.70(s, 1H).

Compound 383. ¹H NMR (600 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 5.17 (s,2H), 7.21-7.27 (m, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H),7.52-7.56 (m, 2H), 7.58 (t, J=7.0 Hz, 1H), 7.66 (t, J=6.8 Hz, 1H),7.88-7.91 (m, 2H), 10.36 (s, 1H).

Compound 384. ¹H NMR (600 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 5.18 (s,2H), 7.22 (s, 1H), 7.23-7.28 (m, 2H), 7.32 (d, J=9.2 Hz, 1H), 7.43-7.48(m, 2H), 7.83 (d, J=2.9 Hz, 1H), 10.86 (s, 1H).

Compound 385. ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.35 (s, 3H), 5.18 (s,2H), 7.20-7.27 (m, 3H), 7.29-7.34 (m, 1H), 7.40-7.47 (m, 2H), 7.80 (d,J=2.2 Hz, 1H), 10.84 (s, 1H).

Compound 386. ¹H NMR (600 MHz, DMSO-d6) δ ppm 5.17 (s, 3H), 7.20-7.27(m, 4H), 7.31 (d, J=9.2 Hz, 1H), 7.42 (dd, J=9.0, 2.6 Hz, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 10.74 (s, 1H).

Compound 387. ¹H NMR (600 MHz, DMSO-d6) δ ppm 5.31 (s, 2H), 7.24 (d,J=9.2 Hz, 1H), 7.51-7.55 (m, 2H), 7.57-7.60 (m, 1H), 7.66 (td, J=7.2,3.1 Hz, 2H), 7.70-7.74 (m, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.85-7.91 (m,3H), 10.37 (s, 1H).

Compound 388. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.32 (s, 2H), 7.27 (d,J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.67 (d, J=7.4 Hz, 1H),7.69-7.75 (m, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.85(s, 1H), 10.86 (s, 1H).

Compound 389. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.32 (s, 2H), 7.27 (d,J=8.9 Hz, 1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H),7.71 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.85 (s,1H), 10.85 (s, 1H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 69.4, 94.3, 114.9,119.5, 121.2, 121.6, 123.8, 124.6, 124.7, 126.0, 128.7, 129.4, 129.5,129.6, 131.4, 132.4, 133.4, 135.2, 138.1, 150.1, 161.2, 164.7.

Compound 390. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.31 (s, 2H), 7.27 (d,J=8.7 Hz, 1H), 7.43 (dd, J=8.9, 1.4 Hz, 1H), 7.64-7.73 (m, 2H), 7.77 (d,J=6.9 Hz, 1H), 7.80-7.86 (m, 2H), 10.77 (s, 1H). ¹³C NMR (126 MHz,DMSO-d6) δ ppm 69.9, 115.4, 116.3, 119.9, 121.6, 122.1, 123.4, 124.3,125.2, 130.1, 130.8, 131.8, 133.0, 138.1, 138.6, 150.4, 166.3.

Compound 391. ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.0 Hz, 3H),5.57 (d, J=6.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.18-7.29 (m, 2H), 7.38(dt, J=15.2, 7.70 Hz, 4H), 7.72-7.85 (m, 2H), 8.23-8.34 (m, 2H), 10.55(s, 1H).

Compound 392. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.32 (s, 3H), 6.47 (d,J=8.5 Hz, 1H), 7.30-7.46 (m, 5H), 7.77 (t, J=8.0 Hz, 1H), 8.15 (d, J=8.2Hz, 1H), 8.20-8.34 (m, 2H), 9.90 (s, 1H).

Compound 393. ¹H NMR (300 MHz, DMSO-d6) δ ppm 5.30 (s, 2H), 7.25 (d,J=9.1 Hz, 1H), 7.32-7.43 (m, 1H), 7.63-7.73 (m, 2H), 7.75-7.86 (m, 4H),8.24-8.36 (m, 2H), 10.62 (s, 1H).

Compound 400. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.39-3.51 (m, 2H)3.51-3.62 (m, 2H) 3.64-3.85 (m, 2H) 4.24-4.44 (m, 2H) 6.83 (d, J=8.8 Hz,1H) 7.45-7.72 (m, 3H) 7.72-8.09 (m, 2H) 8.41 (d, J=2.2 Hz, 1H) 10.33 (s,1H) 13.06 (br. s, 1H). ¹³C NMR (DMSO-d6) δ ppm 58.1, 64.9, 68.8, 69.7,71.3, 110.3, 127.8, 129.6, 130.0, 130.5, 131.7, 131.7, 137.8, 138.5,159.2, 167.4, 167.4.

Compound 401. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.22 (s, 3H) 3.38-3.50 (m,2H) 3.51-3.61 (m, 2H) 3.64-3.85 (m, 2H) 4.13-4.50 (m, 2H) 6.87 (d, J=8.8Hz, 1H) 7.91 (dd, J=8.8, 2.7 Hz, 1H) 8.36 (d, J=2.4 Hz, 1H) 10.84 (s,1H).

Compound 402. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.23 (s, 2H) 3.36-3.52 (m,2H) 3.52-3.64 (m, 2H) 3.64-3.87 (m, 2H) 4.26-4.44 (m, 2H) 6.87 (d, J=8.8Hz, 1H) 7.89 (dd, J=8.9, 2.6 Hz, 1H) 8.34 (d, J=2.4 Hz, 1H) 10.83 (s,1H).

Compound 404. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.32-3.51 (m, 3H)3.51-3.64 (m, 3H) 3.66-3.87 (m, 3H) 4.13-4.47 (m, 2H) 6.86 (d, J=8.8 Hz,1H) 7.88 (dd, J=8.9, 2.35 Hz, 1H) 8.33 (d, J=2.2 Hz, 1H) 10.74 (s, 1H).

Compound 405. ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.38-3.51 (m, 4H)3.51-3.64 (m, 2H) 3.66-3.85 (m, 2H) 4.24-4.45 (m, 2H) 6.86 (d, J=9.3 Hz,1H) 7.90-8.02 (m, 2H) 8.37-8.52 (m, 2H) 10.58 (d, J=14.6 Hz, 2H).

Compound 406. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.34 (br. s, 2H) 3.45 (dd,J=5.5, 3.7 Hz, 2H) 3.59 (dd, J=5.4, 3.8 Hz, 2H) 3.67-3.86 (m, 2H)4.22-4.39 (m, 2H) 7.21 (d, J=9.1 Hz, 1H) 7.46 (dd, J=8.9, 2.3 Hz, 1H)7.52-7.65 (m, 3H) 7.67 (dd, J=7.4, 1.10 Hz, 1H) 7.91 (d, J=6.9 Hz, 1H)8.72 (d, J=2.3 Hz, 1H) 10.56 (s, 1H).

Compound 407. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.24 (s, 3H) 3.44 (br. s,2H) 3.58 (br. s, 2H) 3.75 (br. s, 2H) 4.34 (br. s, 2H) 7.25 (d, J=8.9Hz, 1H) 7.41 (br. s, 1H) 8.65 (br. s, 1H) 11.10 (s, 1H).

Compound 412. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.23 (d, J=8.9 Hz, 2H)7.62 (s, 2H) 7.73 (d, J=8.7 Hz, 2H) 7.84 (s, 1H) 10.96 (s, 1H).

Compound 413. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.23 (m, J=8.6 Hz, 2H),7.62 (s, 2H), 7.72 (m, J=8.6 Hz, 2H), 7.84 (s, 1H), 10.95 (s, 1H). ¹³CNMR (126 MHz, DMSO-d6) δ ppm 118.5, 121.1, 122.0, 122.3, 124.4, 129.2,129.9, 132.3, 132.6, 133.8, 133.8, 135.8, 136.0, 151.1, 159.2, 161.7,165.2.

Compound 414. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.21 (d, J=9.5 Hz, 2H)7.58 (s, 2H) 7.70 (d, J=7.9 Hz, 2H) 7.81 (s, 1H) 10.87 (s, 1H). ¹³C NMR(126 MHz, DMSO-d6) δ ppm 67.5, 121.1, 122.0, 122.2, 123.4, 124.4, 130.7,132.3, 132.6, 136.0, 137.0, 138.2, 151.0, 159.2, 163.2, 166.4.

Compound 415. ¹H NMR (300 MHz, CDCl₃) δ ppm 3.70 (br. s, 2H) 6.71-6.83(m, 2H) 6.86-6.98 (m, 2H), 7.35 (s, 2H) 7.53 (s, 1H).

Compound 416. ¹H NMR (300 MHz, CDCl₃) δ ppm 5.55 (s, 2H) 6.95 (d, J=9.1Hz, 1H) 7.48-7.58 (m, 1H) 7.66-7.75 (m, 1H) 7.79 (s, 1H) 8.43 (dd,J=9.1, 2.7 Hz, 1H) 9.10 (d, J=2.7 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ ppm67.6, 111.5, 112.8, 118.4, 129.4, 131.4, 131.8, 132.2, 134.3, 137.6,144.6.

Compound 417. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.26 (s, 2H), 7.23 (d,J=8.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.46-7.63 (m, 7H), 7.66 (t, J=7.5Hz, 1H), 7.85-7.95 (m, 2H), 10.37 (s, 1H).

Compound 418. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.26 (d,J=8.9 Hz, 1H) 7.34 (d, J=7.5 Hz, 1H) 7.39-7.61 (m, 5H) 7.83 (d, J=2.5Hz, 1H) 10.87 (s, 1H).

Compound 419. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.26 (d,J=8.9 Hz, 1H) 7.34 (d, J=7.7 Hz, 1H) 7.38-7.62 (m, 5H) 7.82 (d, J=1.9Hz, 1H) 10.86 (s, 1H).

Compound 420. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.25 (d,J=8.9 Hz, 1H) 7.33 (d,

J=7.7 Hz, 1H) 7.44 (dd, J=8.8, 2.2 Hz, 1H) 7.49 (d, J=9.3 Hz, 2H)7.52-7.59 (m, 1H) 7.83 (d, J=2.1 Hz, 1H) 10.79 (s, 1H). ¹³C NMR (126MHz, DMSO-d6) δ ppm 54.9, 69.3, 119.5, 121.2, 121.6, 122.9, 126.2,130.3, 130.5, 132.5, 139.5, 148.5, 150.0, 162.6, 166.9.

Compound 421. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.24 (d,J=8.9 Hz, 1H) 7.31-7.44 (m, 2H) 7.47-7.61 (m, 3H) 7.79-7.88 (m, 2H) 8.29(d, J=7.7 Hz, 1H) 8.35 (d, J=8.1 Hz, 1H) 10.64 (s, 1H).

Compound 422. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.21-7.31 (m,1H) 7.34 (d, J=7.7 Hz, 1H) 7.44-7.54 (m, 4H) 7.56 (t, J=7.7 Hz, 1H)7.77-7.94 (m, 2H) 8.35-8.45 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ ppm56.0, 69.5, 111.1, 111.6, 111.9, 121.5, 128.3, 134.1, 144.8, 149.2,149.4, 166.9, 166.9.

Compound 423. ¹H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 2H) 7.25 (d,J=8.9 Hz, 1H) 7.34 (d, J=7.7 Hz, 1H) 7.48-7.69 (m, 5H) 8.00 (d, J=2.5Hz, 1H) 8.18-8.26 (m, 1H) 8.72-8.79 (m, 1H).

Compound 424. 10.66 (s, 1H). 1H NMR (500 MHz, DMSO-d6) δ ppm 5.27 (br.s, 2H) 7.25 (d, J=8.7 Hz, 1H) 7.34 (br. s, 1H) 7.41-7.58 (m, 5H) 7.60(d, J=3.9 Hz, 2H) 7.88 (br. s, 1H) 8.85 (d, J=16.9 Hz, 2H) 10.55 (br. s,1H).

Compound 425. ¹H NMR (500 MHz, CDCl₃) δ ppm 3.88-3.96 (m, 7H), 5.44 (s,2H), 6.89 (d, J=2.0 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 7.05 (dd, J=8.2,2.0 Hz, 1H), 8.37 (dd, J=9.1, 2.9 Hz, 1H), 9.11 (d, J=2.8 Hz, 1H). ¹³CNMR (126 MHz, CDCl₃) δ ppm 56.0, 69.5, 111.1, 111.6, 111.9, 121.5,128.3, 134.1, 144.8, 149.2, 149.4, 166.9.

Compound 427. ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.12 (s, 4H) 5.28 (s, 2H)7.20 (d, J=8.9 Hz, 1H) 7.39 (dd, J=8.8, 2.2 Hz, 1H) 7.66 (d, J=7.7 Hz,1H) 7.70 (s, 1H) 7.76-7.79 (m, 1H) 7.79-7.89 (m, 2H).

Specific compounds of the invention include the following structures andtheir pharmaceutical salts.

Example 2

This Example demonstrates screening methods for the identification andselection of compounds effective for treating, inhibiting, and/orkilling bacteria, such as antibiotic resistant strains of bacteria. Thescreening methods include using TEM-1, P99, OXA-10, BlaR, and PBP2aassay protocols. TEM-1, P99, and OXA-10 are representative members ofclass A, class C, and class D β-lactamases. BlaR and PBP2a arepenicillin-binding proteins. BlaR is a key β-lactam antibioticsensor/signal transducer involved in manifestation of antibioticresistance in certain Gram positive bacteria, including MRSA. In Table10, for the results of the PBP2a assays, the term “X” refers to aninhibitory concentration of about 5 to about 1 mM, the term “XX” refersto an inhibitory concentration of about 1 to about 0.1 mM, and the term“XXX” refers to an inhibitory concentration of less than about 0.1 mM.

β-Lactamase Assays (TEM-1; P99; and OXA-10):

The activity of the compounds of the invention (inhibitors) towardβ-lactamases was evaluated using 96 well plates. The reaction mixtureincluded 10 mM sodium phosphate, pH 7.0, 150 mM sodium chloride, 0.01%Triton X-100, 100 nitrocefin, 10 nM of β-lactamases (class A: TEM-1;class C: P99, or class D: OXA-10), and variable concentrations of theinhibitors in a total volume of 100 μL. β-Lactamases were pre-incubatedwith the compounds at room temperature for 5 minutes, and the assay wasinitiated by the addition of nitrocefin. The inhibition of the enzymeactivity by the compounds was determined by monitoring color change(from yellow to red) of nitrocefin after 20 minutes. Stock solutions ofthe compounds were prepared in dimethyl sulfoxide (DMSO). No more than5% DMSO was present in assays, unless noted otherwise.

BlaR assay:

The surface domain of BlaR (1 μM) was added to each inhibitor (atvarious concentrations) in 100 mM sodium phosphate, 50 mM sodiumbicarbonate, at pH 7.0. The reaction mixtures were incubated at roomtemperature for 20 minutes. BOCILLIN FL, a fluorogenic ligand, was addedto a concentration of 20 μM in a final volume of 20 μL. The mixtureswere incubated at 37° C. for 5 minutes, at which point the reactionswere quenched by the addition of 15 μL of the SDS sample buffer (125 mMTris, 4% SDS, 20% glycerol, 2% 2-mercaptoethanol, pH 6.8), and wereboiled for 4 minutes. The samples were loaded onto 15% SDS-PAGE, the gelwas developed and scanned using a Storm 840® Fluorimager. Thefluorescent bands of BOCILLIN FL-labeled BlaR^(S) were analyzed by ImageQuant 5.2 software.

PBP2 Assay:

The PBP2 assay was performed according to the methods ofVillegas-Esterada et al. (J. Am. Chem. Soc. 2008, 130, 9212-9213).

TABLE 10 Cmpd DOC-mg DH-DOC Mol. Wt. DHD-mg TEM-1 P99 OXA-10 BlaR PBP2a* 0  1 600  2 C14H11NO3 1600 M.w.: 241.07  3 1800  4 1100  5 700  6 400 7 C14H12N2O3 200 M.w.: 256.08  8 C15H10F3NO3 800 M.w.: 309.06  9 400 10  11 C8H11NO3 200 M.w.: 169.07  12 1700  13 1600  14 1100  15 1820 16 50  17 420  18 1200  19 C8H13NO3 510 M.w.: 171.09  20 C11H9NO5 1210M.w.: 235.05  21 C19H20N2O4 710 M.w.: 340.14  22 C18H20N2O3 1010 M.w.:312.15  23 1020  24 C16H9F6NO3 2025 M.w.: 377.05  25 C16H15NO5 1059M.w.: 301.10  26 C16H13NO5 490 M.w.: 299.08  27 C15H10F3NO4 450 M.w.:325.06  28 C15H12N2O4 880 M.w.: 284.08  29 C25H24N2O6 1120 M.w.: 448.16 30 C14H10FNO3 740 M.w.: 259.06  31 C15H18N2O4 1560 M.w.: 290.13  32C14H18N2O3 2130 M.w.: 262.13  33 C13H10N2O3 1258 M.w.: 242.07  34C12H7F6NO3 2240 M.w.: 327.03  35 C12H13NO5 2105 M.w.: 251.08  36C12H11NO5 1750 M.w.: 249.06  37 C11H8F3NO4 2102 M.w.: 275.04  38C11H10N2O4 1650 M.w.: 234.06  39 C21H22N2O6 1000 M.w.: 398.15  40C10H8FNO3 1500 M.w.: 209.05  41 C18H17NO3 1020 M.w.: 295.12  42C18H14N2O3 650 M.w.: 306.10  43 C18H18N2O4 750 M.w.: 326.13  44C15H9ClF3NO3 220 x M.w.: 343.02  45 C15H10N2O3 540 M.w.: 266.07  46C15H9ClF3NO3 1250 M.w.: 343.02  47 C18H13NO4 369 x M.w.: 307.08  48C15H11NO5 250 M.w.: 285.06  49 C18H17ClN2O3 550 M.w.: 344.09  50C16H15NO5 1150 M.w.: 301.10  51 C14H15NO3 1150 M.w.: 245.11  52C14H12N2O3 2600 M.w.: 256.08  53 C14H16N2O4 x M.w.: 276.11  54C11H7ClF3NO3 1980 M.w.: 293.01  55 C11H8N2O3 1350 M.w.: 216.05  56C11H7ClF3NO3 M.w.: 293.01  57 C14H11NO4 M.w.: 257.07  58 C11H9NO5 M.w.:235.05  59 C14H15ClN2O3 M.w.: 294.08  80  81 C18H19N3O5 300 M.w.: 357.13 82 C16H8F6N2O5 1820 M.w.: 422.03  83 C16H14N2O7 850 M.w.: 346.08  84C15H9F3N2O6 1980 M.w.: 370.04  85 C15H8ClF3N2O5 2800 x M.w.: 388.01  86C15H8ClF3N2O5 3200 xx x M.w.: 388.01  87 C16H9ClF3NO5 10 M.w.: 387.01 88 C16H9ClF3NO5 740 M.w.: 387.01  89 C15H5Br4ClF3NO3 1600 xx xxx xxxM.w.: 659.27  90 C15H8ClF4NO3 1200 M.w.: 361.68  91 C15H8ClF4NO3 M.w.:361.68  92/93 C16H11ClF3NO3 1500 xx M.w.: 357.71  93/92 C16H11ClF3NO31500 xx M.w.: 357.71  94 C15H15ClF3NO3 300 x M.w.: 349.73  95/96C16H17ClF3NO3 600 x xxx xx M.w.: 363.76  96/95 C16H17ClF3NO3 600 x xxxxx M.w.: 363.76  97 C25H17ClF3NO7 100 x x M.w.: 535.06  98 C15H13ClF3NO71000 M.w.: 411.03  99 C17H11ClF3NO3 220 M.w.: 369.04 100 C17H11ClF3NO3100 x M.w.: 369.04 101 C9H13NO4S2 M.w.: 263.03 102 C24H18ClF3N2O5 M.w.:506.09 103 C24H18ClF3N2O5 M.w.: 506.09 104 C23H15ClF3N3O7 M.w.: 537.06105 C23H15ClF3N3O7 M.w.: 537.06 106 C23H15ClF3N3O7 M.w.: 537.06 107C23H15ClF3N3O7 M.w.: 537.06 108 C23H19NO8 800 x M.w.: 437.40 109C13H15NO8 1200 x M.w.: 313.26 110 C14H11NO6 100 x M.w.: 289.24 111C14H11NO6 600 x M.w.: 289.24 112 C13H17NO4 1400 M.w.: 251.28 113C19H21NO4 100 M.w.: 327.37 114 C9H8N2O3S3 1100 M.w.: 288.37 115C12H15NO7S2 10 M.w.: 349.03 116 C22H19ClN2O6S3 400 M.w.: 538.01 117C22H21ClN2O7S3 200 M.w.: 556.02 118 C16H14N2O7S3 350 x xxx x M.w.: 442119 C7H8O4S2 980 x M.w.: 219.99 120 C6H7NO3S2 600 xx x Mol. Wt.: 204.99121 C6H6O4S2 1800 x Mol. Wt.: 205.97 122 C12H17NO8S2 1700 x Mol. Wt.:367.04 123 C9H13NO4S2 300 Mol. Wt.: 263 124 C9H13NO4S2 400 Mol. Wt.: 263125 C10H15NO4S2 300 Mol. Wt.: 277 126 C10H15NO4S2 xx Mol. Wt.: 277 127C15H17NO5S2 200 xx Mol. Wt.: 355 128 C15H17NO5S2 200 x Mol. Wt.: 355 129C10H15NO5S2 350 x Mol. Wt.: 293.36 130 C10H15NO5S2 Mol. Wt.: 293 131C17H22N2O3S2 Mol. Wt.: 366 132 C17H22N2O3S2 Mol. Wt.: 366 133C16H19NO4S2 200 x Mol. Wt.: 353 134 C16H19NO4S2 10 x Mol. Wt.: 353 135C16H19NO4S2 300 x Mol. Wt.: 353.46 136 C16H19NO4S2 650 x Mol. Wt.: 353137 C15H15NO4S2 10 Mol. Wt.: 337.42 138 C15H15NO4S2 10 xxx xxx x Mol.Wt.: 337.42 139 C15H16N2O7S2 850 x Mol. Wt.: 400.43 140 C15H14N2O6S2 200xx xx xx x M.w.: 382.41 141 C9H11NNa2O6S3 100 x M.w.: 371.36 142C15H26N2O5S3 100 x M.w.: 410.58 143 C15H16N2O7S2 500 x M.w.: 400.43 144C15H14N2O6S2 120 x M.w.: 382.41 145 C15H13NO5S2 300 x M.w.: 351.02 146C15H13NNa2O6S2 650 x M.w.: 413.00 147 148 149 150 C15H25NO3 1400 M.w.:267 151 C16H18F3NO3 2200 M.w.: 329 152 C11H19NO4 100 M.w.: 229 153C14H25NO3 850 M.w.: 255 154 C15H18FNO3 1100 M.w.: 279 155 C17H22ClNO52400 M.w.: 356 156 C16H18N2O3 1400 M.w.: 286 157 C17H23NO5 1700 M.w.:321 158 C13H23NO4 100 x M.w.: 257 159 C12H21NO4 100 M.w.: 243 160C12H21NO4 100 Mol. Wt.: 243 161 C13H23NO4 100 Mol. Wt.: 257 162C17H23NO5 160 Mol. Wt.: 321 163 C15H18FNO3 420 Mol. Wt.: 279 164C17H21NO5 1800 Mol. Wt.: 319 165 C15H18FNO3 250 Mol. Wt.: 279 166C15H5ClF7NO3 450 Mol. Wt.: 416 167 C16H11F4NO5 100 Mol. Wt.: 373 168C15H6F7NO3 120 Mol. Wt.: 381 169 C15H6F7NO3 210 Mol. Wt.: 381 170C11H9F4NO4 100 Mol. Wt.: 295 171 C13H13F4NO3 200 Mol. Wt.: 307 172C14H13F4NO3 200 Mol. Wt.: 319 173 C15H18N2O6 200 Mol. Wt: 322 174C14H18N2O3 300 Mol. Wt.: 262 175 C17H23NO3 700 Mol. Wt.: 289 176C16H20ClNO4 400 Mol. Wt.: 326 177 C21H23NO4 800 Mol. Wt.: 353 178C16H21NO4 300 Mol. Wt.: 291 179 Mol. Wt.: 354 1100 180 C18H25NO4 700Mol. Wt.: 319 181 C20H30NO6P 1000 Mol. Wt.: 411 182 C22H24ClNO4 1000Mol. Wt.: 402 183 C12H21NO4 300 Mol. Wt.: 243 184 C16H21NO4 150 Mol.Wt.: 291 185 C23H35NO4 40 Mol. Wt.: 390 186 C16H20ClNO3 100 Mol. Wt.:310 187 C18H23Cl2NO4 150 Mol. Wt.: 388 188 C16H20ClNO3 200 Mol. Wt.: 310189 C13H23NO5 100 Mol. Wt.: 273 190 C13H23NO5 130 Mol. Wt.: 273 191C18H25NO5 650 Mol. Wt.: 335 192 C18H25NO4 400 Mol. Wt.: 319 193C18H24N2O7 200 Mol. Wt.: 380 194 C18H24N2O7 1100 Mol. Wt.: 380 195C14H13Br4NO3 300 Mol. Wt.: 563 196 C15H6Br4F3NO3 800 xx xx Mol. Wt.: 625197 C11H9Br4NO4 400 Mol. Wt.: 539 198 C13H13Br4NO3 Mol. Wt.: 551 199C14H6Br4FNO3 300 Mol. Wt.: 575 200 C16H10Br4ClNO5 700 Mol. Wt.: 651 201C15H5Br4N2NaO3 2700 xx xxx xx x Exact Mass: 600 202 C16H11Br4NO5 600Mol. Wt.: 617 203 C12H11Br4NO4 Mol. Wt.: 553 204 C11H9Br4NO4 Mol. Wt.:539 205 C11H9Br4NO4 Mol. Wt.: 539 206 207 C16H11Br4NO5 Mol. Wt.: 617 208C14H6Br4FNO3 Mol. Wt.: 575 209 C16H9Br4NO5 Mol. Wt.: 615 210C14H6Br4FNO3 150 Mol. Wt.: 575 211 C17H11Br4Cl2NO4 Mol. Wt.: 684 212 213214 C15H6Br4F3NO3 Mol. Wt.: 625 215 C11H9Br4NO4 300 Mol. Wt.: 539 216C13H13Br4NO3 1000 Mol. Wt.: 551 217 C12H11Br4NO4 300 xx Mol. Wt.: 553218 C14H6Br4N2O6 200 Mol. Wt.: 618 219 C13H6Br4N2O3 300 Mol. Wt.: 558220 C16H11Br4NO3 500 Mol. Wt.: 585 221 C15H8Br4ClNO4 300 Mol. Wt.: 621222 C20H11Br4NO4 900 xx Mol. Wt.: 649 223 C15H9Br4NO4 1400 xxx xxx xxxExact Mass: 583 224 C15H8Br5NO3 200 Mol. Wt.: 650 225 C17H13Br4NO4 Mol.Wt.: 615 226 C19H18Br4NO6P 300 Mol. Wt.: 707 227 C21H10Br4ClNO3 100 xxxx xxx Mol. Wt.: 579 228 C11H9Br4NO4 100 Mol. Wt.: 539 229 C15H9Br4NO4100 Mol. Wt.: 587 230 C22H21Br4NO3 200 Exact Mass: 662.8 231C15H8Br4ClNO3 200 Mol. Wt.: 605 232 C15H8Br4ClNO3 400 x x Mol. Wt.: 605233 C12H11Br4NO5 Mol. Wt.: 569 234 C12H11Br4NO5 Mol. Wt.: 569 235C17H13Br4NO5 Mol. Wt.: 631 236 C17H13Br4NO4 150 Mol. Wt.: 615 237C17H12Br4N2O7 140 Mol. Wt.: 676 238 C17H12Br4N2O7 200 x x Mol. Wt.: 676239-Na C21H11Br4ClNNaO4 1000 xxx xxx xxx xxx M.w.: 719.38 240 C18H24N2O7400 Exact Mass: 380 241 242 C16H18N2O3 200 Exact Mass: 286 243C22H24ClNO4 700 x Exact Mass: 401 244 C16H21NO4 100 Exact Mass: 291 245C16H20ClNO3 400 Exact Mass: 309 246 C16H17ClF3NO3 660 xx Exact Mass: 363247 C16H18F3NO3 500 Exact Mass: 329 248 C18H24N2O7 700 Exact Mass: 380249 C8Br4O3 10 Exact Mass: 460 250 C13H12ClNO 100 Exact Mass: 233 251C21H12ClF4NO4 100 x Exact Mass: 453 252 C14H5Br4ClNNaO4 300 Exact Mass:624.7  5 g 253 C21H12Cl5NO4 10 xxx xxx xxx xx Exact Mass: 516.9 254C15H9Cl4NO4 400 xx Exact Mass: 406.9 255 C15H6Cl4N2O3 300 Exact Mass:401.9 256 257 C15H8Cl5NO3 1200 x Exact Mass: 424.9 258 C15H5Cl5F3NO31600 xxx xx xx Exact Mass: 478.9 259 C15H10Cl4N2O5S 2100 Exact Mass:469.9 260 261 C14H6Cl5NO4 1400 Exact Mass: 426.9 262 C15H9Cl4NO4 1200 xExact Mass: 406.9 263 C19H18Cl4NO6P 2300 Exact Mass: 527.0 264C16H11Cl4NO5 1800 Exact Mass: 436.9 265 C22H23Cl4NO4 700 xxx xxx xxxExact Mass: 505.0 266 267 C17H12Cl4N2O7 100 x Exact Mass: 495.9 268C20H11Cl4NO4 1000 xxx xx x Exact Mass: 468.9 269 C15H4Br4N2O2 300 ExactMass: 559.7 270 C22H27NO4 900 xxx xxx xxx xx x Exact Mass: 369.2 271C22H23F4NO4 900 xxx xxx xxx xxx x Exact Mass: 441.2 272 C21H16ClNO4 800Exact Mass: 381.1 273 C14H5Br4N2NaO5 100 Exact Mass: 619.7 274C22H23Br4NO4 1700 xxx xxx xxx Exact Mass: 680.8 5200 275 C19H21NO4 700Exact Mass: 327.1 276 277(1-4) C21H10Cl5NOS2 100 xxx xxx x Exact Mass:530.9 100 278 C21H12Br4ClNO3S 500 xxx xxx xxx xxx xxx Exact Mass: 708.7279/2 C22H27NO3S 200 xxx xxx Exact Mass: 385.2 280(1-2) C22H23Cl4NOS3200 x xxx xxx xxx xx Exact Mass: 553 100 281 C22H21Br4NOS2 120 xxx ExactMass: 694.8 100 282 C24H27Cl4NO4 x x xxx Exact Mass: 533.1 283C14H8ClNO3 Exact Mass: 273 284 C24H31NO4 100 Exact Mass: 397.2 285C24H27F4NO4 100 Exact Mass: 469.2 286 C24H27Cl4NO4 Exact Mass: 533.1 287C24H27Br4NO4 600 Exact Mass: 708.9 288 C30H43NO4 500 x x Exact Mass:481.3 289 C30H39F4NO4 1200 xx xxx xxx Exact Mass: 553.3 290 C30H39Cl4NO4500 x xxx xxx xxx Exact Mass: 617.2 291 C30H39Br4NO4 1000 xxx xxx xxx xxExact Mass: 793 292 C23H25Br4NO4 200 Exact Mass: 694.9 293 C14H20ClNO3200 Exact Mass: 285.1 294 C15H9Br4NO4 2500 Mol. Wt.: 586.9 295 C15H15NO320 g Mol. Wt.: 257.3 296 10 xx 297 C23H31NO3 13 Exact Mass: 369.2 298C14H22ClNO 1100 Exact Mass: 255.1 299 C14H22ClNO 5 Exact Mass: 255.1 300C22H26ClNO4 700 xxx xx xx xxx Mol. Wt: 403.9 301 C22H22ClF4NO4 1000 xxxxx xxx xxx xxx Mol. Wt.: 475.9 302-2 C22H22Cl5NO4 300 xxx xx ExactMass: 539 303 C22H22Br4ClNO4 1400 xx Mol. Wt: 719.5 304 C23H29NO4 100Mol. Wt: 383.5 305 C23H25F4NO4 1200 xx xx Mol. Wt: 455.4 306C23H25Cl4NO4 100 Mol. Wt: 521.3 307 C23H25Br4NO4 200 xxx x Mol. Wt:699.1 308 C15H25NO- Exact Mass: 235.2 309 C23H29NO3S 100 Mol. Wt: 399.5310 C16H25NO3 300 Mol. Wt: 279.4 311 C16H27NO Mol. Wt: 249.4 312C16H24ClNO3 10 g Mol. Wt: 313.8 313 C16H26ClNO Mol. Wt: 283.8 314C25H35NO3 100 Mol. Wt: 397.6 315 C17H29NO- 2100 Mol. Wt: 263.4 316C25H29Br4NO4 800 xx Mol. Wt: 727.1 317 C14H10ClNO3 1700 Mol. Wt: 275.7318 C25H33NO4 1000 xxx Exact Mass: 411.2 319 C25H29F4NO4 500 xxx ExactMass: 483.2 600 320 C25H29Cl4NO4 Exact Mass: 547.1 321 C25H33NO3S ExactMass: 427.2 322 C25H29Cl4NO3S Exact Mass: 563.1 323 C19H19NO6 1000 xxxExact Mass: 357.1 324 C19H19NO5S 200 xx xx Exact Mass: 373.1 325C19H20N2O5 1200 Exact Mass: 356.1 326 C20H22N2O5 200 Exact Mass: 370.2327 C20H28O7 100 Exact Mass: 380.2 328 C18H25NO4 Exact Mass: 319.2 329C24H27Br4NO4 1200 xxx 713.09 330 C13H22O6 10 Mol. Wt: 274.3 331C19H19NO5 1900 Mol. Wt.: 341.36 332 C19H15F4NO5 700 Mol. Wt.: 413.32 333C19H15Cl4NO5 3000 x Mol. Wt.: 479.14 334 C19H15Br4NO5 600 x Mol. Wt.:656.94 335 C9H8ClNO4 M.w. 229 336 C17H17NO4S2 300 Mol. Wt.: 363.45 337C20H27NO5 1400 Mol. Wt.: 361.43 338 339 15 g 340 341 342 343 C21H26N2O41200 x x Mol. Wt.: 370.44 344 C21H22F4N2O4 400 x Mol. Wt: 442.4 345C21H22Cl4N2O4 1800 xxx xxx xxx Mol. Wt.: 508.22 346 C21H22Br4N2O4 1800xxx xxx xxx x Mol. Wt.: 686.03 347 348 C21H24ClNO6 100 Mol. Wt.: 421.87349 C21H20ClF4NO6 500 Mol. Wt.: 493.83 350 C21H20Cl5NO6 700 x Mol. Wt.:559.65 351 C21H20Br4ClNO6 600 Mol. Wt.: 737.46 352 353 C21H22ClNO6 100Mol. Wt.: 419.86 354 C21H18ClF4NO6 100 355 C21H18Cl5NO6 100 xxx Mol.Wt.: 557.64 Mol. 356 C21H18Br4ClNO6 100 x x xx Mol. Wt.: 735.44 357C21H26N2O5 170 Mol. Wt.: 386.44 358 C21H22Cl4N2O5 300 xxx Mol. Wt.:524.22 359 C21H22F4N2O5 500 Mol. Wt: 458.4 360 C21H22Br4N2O5 1100 xx xxxx Mol. Wt.: 702.03 361 C12H12N2O M.w.: 200.24 362 C19H16N2O2 1000 Mol.Wt.: 304.34 363 C20H12F4N2O4 200 Mol. Wt.: 420.31 364 C20H12Cl4N2O4 1200x Mol. Wt.: 486.13 365 C20H12Br4N2O4 1700 xx Mol. Wt.: 663.94 366 367368 C20H12Cl4N2O5 300 Mol. Wt.: 502.13 369 C20H12Br4N2O5 300 Mol. Wt.:679.94 370 C14H12ClNO3  7 g M.w.: 277.7 371 C14H12ClNO3 M.w.: 277.7 372C14H9ClF3NO3 10 g M.w.: 331.67 373 C14H12ClNO3 M.w.: 277.7 374C14H12ClNO3 12 g M.w.: 277.7 375 C14H9ClF3NO4 M.w.: 347.67 376C14H14ClNO M.w.: 247.72 377 C14H14ClNO 4500 M.w.: 247.72 378C14H11ClF3NO2 M.w.: 317.69 379 C22H18ClNO4 800 M.w.: 395.84 380C22H14ClF4NO4 1200 M.w.: 467.8 381 C22H14Cl5NO4 100 x xxx M.w.: 533.62382 C22H14Br4ClNO4 500 xxx xxx xxx xxx M.w.: 711.42 383 C22H18ClNO4 1200M.w.: 395.84 384 C22H14ClF4NO4 1400 M.w.: 467.8 385 C22H14Cl5NO4 2900 xxxx xxx xxx M.w.: 533.62 386 C22H14Br4ClNO4 600 xxx xxx xxx xxx xxx M.w.:711.42 387 C22H15ClF3NO4 200 x x xx Mol. Wt.: 449.81 388 C22H11ClF7NO4400 xx xx Mol. Wt.: 521.77 389 C22H11Cl5F3NO4 900 xxx xxx xxx Mol. Wt.:587.59 390 C22H11Br4ClF3NO4 2100 xxx xxx xxx xxx Mol. Wt.: 765.39 391C22H17ClN2O6 400 M.w.: 440.83 392 C20H15N3O6 900 M.w.: 393.35 393C10H14N2O5 x xxx M.w.: 242.23 394 C10H14N2O5 M.w.: 242.23 395 396 397C10H16N2O3 M.w.: 212.25 398 399 400 C18H20N2O6 700 M.w.: 360.36 401C18H16F4N2O6 700 M.w.: 432.32 402 C18H16Cl4N2O6 1200 M.w.: 498.14 403C18H16Br4N2O6 100 M.w.: 675.95 404 C18H16Br4N2O6 1100 M.w.: 675.95 405C18H19N3O8 1200 M.w.: 405.36 406 C18H20N2O7 200 M.w.: 376.36 407C18H16F4N2O7 300 M.w.: 448.32 408 C18H16Cl4N2O7 120 M.w.: 514.14 409C18H16Cl4N2O7 20 M.w.: 514.14 410 C18H16Br4N2O7 190 M.w.: 691.94 411C14H11ClF3NO2 200 M.w.: 317.69 412 C22H9F10NO4 250 xx M.w.: 541.3 413C22H9Cl4F6NO4 1300 xxx xxx xxx x xxx M.w.: 607.11 414 C22H9Br4F6NO4 1300xxx xxx xxx xxx xxx M.w.: 784.92 5200 415 C22H9Cl4F6NO4 M.w.: 607.11 416C14H9ClN2O3 500 M.w.: 288.69 417 C22H15ClF3NO5 500 xx M.w.: 465.81 418C22H11ClF7NO5 1000 xx xxx x M.w.: 537.77 419 C22H11Cl5F3NO5 1200 xxx xxxxx xxx xxx M.w.: 603.59 420 C22H11Br4ClF3NO5 900 xxx xx xxx xxx xxxM.w.: 781.39 421 C22H14ClF3N2O7 500 M.w.: 510.8 422 C22H14ClF3N2O7 900xx xx xx xxx xxx M.w.: 510.8 423 C21H14ClF3N2O5 500 M.w.: 466.79 424C21H14ClF3N2O5 700 M.w.: 466.79 425 C14H14N2O5 M.w.: 290.27 426C14H16N2O3 M.w.: 260.29 427 C20H15ClF3NO4S2 700 M.w.: 489.92

Example 3

This example identifies if inhibitory activity was detected at a 25mg/mL dose of a compound (selected examples of Compounds 1-414,illustrated above after Table 10) against the bacteria examined. Thesymbol “+” indicates activity against the bacterial while the term “−”indicates there was no observed inhibitory activity. The minimuminhibitory concentrations (MICs) of antibiotics were determined by themicro dilution procedure in Mueller Hinton II Broth (BBL) in accordancewith recommendations of the Clinical and Laboratory Standards Institute(see, Bou et al, Methicillin-Resistant Staphylococcus aureus (MRSA)Protocols in Method in Molecular Biology, 2007, 391, 29-49, SpringerProtocols, Springer Science+Business Media, LLC, Secaucus, N.J., USA).Final bacterial inoculum was 5×10⁵ CFU/mL. Inoculated micro titer plateswere incubated at 35° C. for 24 hours prior to results being recorded.

Table 11 illustrates data showing that minimal inhibitory concentrationswere generally observed at 25 mg/mL. On top of each cell is thecorresponding compound #. The sign below the number indicates growth (+)or no growth (−) at 25 μg/mL. The compounds were dissolved in 100% DMSOto a concentration of 2,000 μf/mL and transferred to Mueller Hintonbroth (200 μL) to a final concentration of 25 μg/mL (final DMSO in thiscase is 1.25%). The compounds that were not readily soluble atconcentration of 2,000 μg/mL were diluted in DMSO to 1,000 μf/mL andtransferred (5 μL instead of 2.5 μL) to Mueller Hinton broth for a finalconcentration in DMSO of 2.5%.

In another test, the compounds were dissolved in 80% DMSO plus 20% ofbuffer (100 mM sodium Phosphate, 0.5% Na₂CO₃) to 2,000 μg/mL and theminimal inhibitory concentrations were determined by diluting thecompounds to 40 μg/mL or lower. However, the resulting minimalinhibitory concentrations were the same as from DMSO when the minimalinhibitory concentrations were in Mueller Hinton broth or Mueller Hintonbroth supplemented with one fifth of buffer (100 mM sodium Phosphate,0.5% Na₂CO₃). The minimal inhibitory concentrations were also determinedunder the above conditions but compounds were first transferred from2,000 μg/mL of DMSO to buffer (100 mM sodium Phosphate, 0.5% Na₂CO₃) tomake a final concentration of 800 μg/mL. However, because some compoundsseparated from the buffer solution, they were transferred to MuellerHinton to arrive at 40 μg/mL and lower. The resulting minimal inhibitoryconcentrations were higher in comparison to two conditions describedabove.

TABLE 11 Bacterial Inhibition by Compounds Described Herein 1 2 3 4 5 67 8 9 10 11 12 + + + + + + + + + + + + 13 14 15 16 17 18 19 20 21 22 2324 + + + + + + + + + + + + 25 26 27 28 29 30 31 32 33 34 3536 + + + + + + + + + + + + 37 38 39 39a 40 41 42 43 44 45 4647 + + + + + + + + + + + + 48 49 50 51 52 53 54 55 56 57 5859 + + + + + + + + + + + + 60 72 81a 81b 81m 82 83 84 85 86 8788 + + + + + + + + + + + + 89 90/91 92/93 94 95/96 97 98 99 100 101 108109 + + + + + + + + + + + + 110 111 112 113 114 115 116 117 118 119 120121 + + + + + + + + + + + + 122 123 124 125 127 128 129 133 134 135 136137 + + + + + + + + + + + + 138 139 140 141 142 143 144 145 146 150 151152 + + + + + + + + + + + + 153 154 155 156 157 158 159 160 161 162 163164 + + + + + + + + + + + + 165 166 167 168 169 170 171 172 173 174 175176 + + + + + + + + + + + + 177 178 179 180 181 182 183 184 185 186 187188 + + + + + + + + + + + + 189 190 191 192 193 194 195 196 197 199 200201 + + + + + + + + + + + + 202 210 215 216 217 218 219 220 221 222 223H223Na + + + + + + + + + + + + 224 2226 227 228 229 230- 231 232 236 237240 242 + + + + + −+ + + + + + + 243 244 245 246 247 248 249 250 255 251251b 252 + + + + + + + + + + + + 253 254 255 257 258 259 261 262 263 264267 268 − + + + + + + + + + + + 269 272 273 275 277-1 277-2 277-3 277-4278 279-2 280-1 280-2 + + + + + + + − − + + − 281 281-1 288 289 290 291292 294-1 294-2 295 296 298 − + − + − − + + + + + + 299 300 301 302302-2 303 304 305 306 307 309 310 − − − − − − + − + + + + 312 314 316317 323 327 333 336 349 451 353 356 + + − + + + + + + + + − 358 359 360362 363 364 366 366-2 369 380 381 384 + + + + + + + + + + + + 386 387400 402 406 407 412 413 414 − + + + + + + − −

Minimum inhibitory concentrations were also determined for the compoundsagainst NRS11 (Mec^(S)) or NRS100 (Mec^(R)) (data not shown). Mec^(S)refers to methicillin sensitive Staphylococcus aureus and Mec^(R) refersto the resistant variant of Staphylococcus aureus. In determining theminimum inhibitory concentrations (MICs) against NRS11 (Mec^(S)) orNRS100 (Mec^(R)), the compounds were dissolved in 100% DMSO to aconcentration of 1,000 μg/mL and diluted directly into Mueller Hinton IIBroth to final 16 μg/mL for MIC testing.

Example 4

This example demonstrates the inhibition of various bacterial strains byselected compounds of the invention. Table 12 illustrates the resultsand the minimal inhibitory concentration (MIC) for S. aureus,Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumonia, andProteus mirabilis. The inoculum is about 1.5×10⁵ CFU/mL. The minimalinhibitory concentrations (MIC) were done in Muller-Hinton II Broth withthe exception of Enterococcus faecalis ATCC 29212, which was done inBrain Heart Infusion Broth. The concentration of DMSO at 200 μg/mL was10%.

TABLE 12 Vanco- Oxa- MIC (μg/mL) of Compound # Strain mycin xillian 239253 265 274 Enterococcus 4 8 200 200 6 100 faecalis ATCC 29212Staphylococcus 1 500 100 50 6 3 aureus NRS100 (COL) Staphylococcus 1000500 25 50 6 3 aureus (COLVA) Staphylococcus 4 500 50 50 6 3 aureus NRS1(Mec^(r). Vani) Staphylococcus 1 <0.5 25 50 6 3 aureus ATCC 29213Escherichia coli 400 400 200 400 ATCC 29194 Pseudomonas 200 200 200 200aeruginosa ATCC 27853 Klebsiella 200 200 200 200 pneumonia ATCC 33495Proteus mirabilis 400 400 200 400 ATCC 35659

Example 5

This example demonstrates the inhibition of methicillin-resistantstrains of S. aureus NRS11 (Mec^(S)) with selected compounds of theinvention. All recited compounds were dissolved in DMSO or in 1% sodiumcarbonate and transferred to micro titer plates to final concentrationsof 1000 μg/mL. The compounds 345, 346, 355, 365, 381, 389, and 385demonstrated significant inhibitory properties, as indicated in Table13.

TABLE 13 Compound # MIC (μg/mL) 324 2,000 325 256 326 2,000 330 2,000331 2,000 332 2,000 334 128 337 2,000 343 256 344 256 345 16 346 <8348 >2,000 350 500 354 500 355 128 357 >2,000 359 1,000 363 >2,000 365 8368 500 379 >2,000 381 16 382 <8 389 <8 385 16 388 128 390 <8 391 500390-1 <8 392 500 390-2 <8 383 128 401 >2,000 403 >2,000 404 >2,000405 >2,000 408 >2,000 409 1,000 410 500

Example 6

This Example demonstrates the inhibition of methicillin-resistantstrains of S. aureus NRS100 (Mec^(R)) with selected compounds of theinvention. The recited compounds were dissolved in DMSO or in 1% sodiumcarbonate and transferred into micro titer plate to final concentrationof 1000 μg/mL. The compounds 345, 346, 355, 365, 381, 382, 385, 389,390, 390-1, and 390-2 demonstrated significant inhibitory activity asindicated below in Table 14.

TABLE 14 MIC MIC MIC Compound (μg/mL) Compound (μg/mL) Compound (μg/mL)324 2,000 389 <8 230 >16 325 256 385 16 253 >16 326 2,000 388 128277-4 >16 330 2,000 390 <8 278 16 331 2,000 391 500 279-2 >16 332 2,000390-1 <8 280-2 8 334 128 392 500 281 4 337 2,000 390-2 4 282 16C 343 256383 128 289 16C 344 256 401 >2,000 290 16C 345 16 403 >2,000 291 16-C346 <8 404 >2,000 299 16 348 >2,000 405 >2,000 300 8 350 500 408 >2,000301 16 354 500 409 1,000 302 4 355 32 410 500 302-2 4 357 >2,000 417 250303 4 359 1,000 418 125 305 16 363 >2,000 419 8 316 16C 365 16 420 8323 >16 368 500 421 250 356 >16 379 >2,000 422 125 386 8 381 32 423 250413 8 382 <8 424 >250 414 4

Table 15 illustrates the inhibition of methicillin-resistant strains ofS. aureus by selected compounds of the invention. The compounds weredissolved in 100% DMSO to 1,000 μg/mL and diluted directly into MuellerHinton II Broth to final 16 μg/mL for MIC testing.

TABLE 15 MIC Compound MIC (μg/mL) Compound (μg/mL) 345 16 302 4 346 8312-2 4 390 8 303 4 390-1 8 386 16 390-2 4 413 16 280-2 8 414 4 281 4419 8 300 16 420 4

Example 7

This Example illustrates the IC₅₀ values of selected compounds forinhibition of β-lactamases. The β-lactamase assays were performedaccording to the methods described in Example 2. These compounds displayinhibitory properties against β-lactamases. Results of the β-lactamaseassays are shown in Table 16.

TABLE 16 DH- IC50s (μM) DOC TEM-1 P99 OXA-10 253 32.3 ± 5.9  104.8 ±8.7  222.0 ± 17.0 265 3.6 ± 0.5 10.3 ± 0.3  9.9 ± 0.8 274 2.4 ± 0.1  3.1± 0.5  5.5 ± 0.5 289 23.1 ± 2.4   1.2 ± 0.1  0.7 ± 0.15 290  0.6 ± 0.06 0.4 ± 0.06  0.5 ± 0.05 291  0.2 ± 0.04  0.2 ± 0.02  0.3 ± 0.06 300  0.7± 0.08 10.3 ± 0.4 30.7 ± 2.8 301 5.1 ± 1.0  9.9 ± 1.7 23.0 ± 2.0 345 4.9± 0.2 27.8 ± 2.9 37.9 ± 6.0 346 2.8 ± 0.3  7.8 ± 1.2 13.1 ± 0.8 382 5.3± 1.1 24.4 ± 1.9 26.6 ± 1.6 386 7.4 ± 1.2 15.3 ± 1.6 31.6 ± 3.5 389 4.5± 0.4 20.2 ± 3.0 44.2 ± 3.4 390 1.9 ± 0.1  6.0 ± 0.8 14.2 ± 1.1 413 27.0± 2.9  31.2 ± 6.4 80.8 ± 7.0 414 4.5 ± 0.4 12.0 ± 0.5 19.5 ± 2.0 419 2.3± 0.1 13.0 ± 2.0 10.8 ± 0.7 420 1.6 ± 0.1  6.9 ± 1.5  8.4 ± 1.1

It should be understood that various changes and modifications to theembodiments described herein will be apparent to those skilled in theart. Such changes and modifications can be made without departing fromthe spirit and scope of the claimed subject matter and withoutdiminishing its intended advantages. It is therefore intended that suchchanges and modifications be covered by the appended claims.

All patents, patent applications, publications, scientific articles, andother documents and materials referenced or mentioned herein areindicative of the levels of skill of those skilled in the art to whichthe invention pertains, and each such referenced document and materialis hereby incorporated by reference to the same extent as if it had beenincorporated by reference in its entirety individually or set forthherein in its entirety. Applicants reserve the right to physicallyincorporate into this specification any and all materials andinformation from any such patents, applications, publications,scientific articles, electronically available information, and otherreferenced materials or documents.

What is claimed is:
 1. A compound of Formula III:

wherein W is absent, oxygen, (C₁-C₂₄)alkylene, or carbonyl; Y is oxygenor sulfur; Z is carbon or nitrogen, provided that when Z is nitrogen, R₈is absent or oxygen; R₁ is carboxylic acid, thiocarboxylic acid, or asalt thereof; R₂ is hydrogen, halo, or nitro; R₃ and R₄ are eachindependently hydrogen, halo, or (C₁-C₂₄)alkyl; R₅ is hydrogen or halo;R₆ is hydrogen or (C₁-C₂₄)alkyl; R₇ is hydrogen or halo; R₈ is absent,hydrogen, or oxygen; R₉ is hydrogen, halo, (C₁-C₂₄)alkyl,—O(C₁-C₂₄)alkyl, or (C₁-C₂₄)alkylene(C₁-C₂₄)cycloalkyl; R₁₀ is hydrogen,cyano, halo, halo(C₁-C₂₄)alkyl, (C₁-C₂₄)alkylhydroxyl, or (C₁-C₂₄)alkyl;R₁₁ is hydrogen; or R₁₀, R₁₁, and the atoms in between form a fused(C₆-C₃₀)aryl; wherein any (C₁-C₂₄)alkyl, (C₁-C₂₄)alkylene, (C₆-C₃₀)aryl,or (C₁-C₂₄)cycloalkyl is optionally substituted on carbon with one ormore oxo, hydroxyl, halo, (C₆-C₃₀)aryl, nitro, cyano, (C₁-C₆)alkoxy, ortrifluoromethyl groups or any combination thereof, and optionallyexchanged on carbon with one or more oxo, imino, or thio groups; or apharmaceutically acceptable salt, a prodrug, or a metabolite thereof. 2.The compound of claim 1 wherein: W is absent, oxygen, —CH₂—, orcarbonyl; Y is oxygen or sulfur; Z is carbon or nitrogen; R₁ is —CO2H,—CS2H, —CO2Na, or —COSH; R₂ is hydrogen, fluorine, chlorine, bromine, ornitro; R₃ and R₄ are each independently hydrogen, fluorine, chlorine,bromine, or methyl; R₅ is hydrogen, fluorine, chlorine, or bromine; R₆is hydrogen or methyl; R₇ is hydrogen or chlorine; R₈ is absent,hydrogen, or oxygen; R₉ is hydrogen, chlorine, —(CH₂)₇CH₃, —(CH₂)₉CH₃,—(CH₂)₁₅CH₃, —O(CH₂)₃CH₃, —CH₂CH(OH)CH₂OCH₂(cyclopropyl); or—CH₂CH(OH)CH₂O(CH₂)₃CH₃; R₁₀ is hydrogen, cyano, chlorine,trifluoromethyl, —CH₂OH, or methyl; R₁₀, R₁₁, and the atoms in betweenform a fused 3-hydroxyphenyl; and R₁₁ is hydrogen.
 3. The compound ofclaim 1 wherein Y is oxygen, Z is carbon, and R₆ is hydrogen.
 4. Thecompound of claim 1 wherein R₁ is —CO₂H or —CO₂Na.
 5. The compound ofclaim 1 wherein R₂ is hydrogen, fluoro, chloro, bromo, or nitro.
 6. Thecompound of claim 1 wherein R₃, R₄, and R₅ are halo.
 7. The compound ofclaim 1 wherein R₃, R₄, and R₅ are hydrogen.
 8. The compound of claim 1wherein R₇ and R₁₁ are each hydrogen.
 9. The compound of claim 1 wherein—WR₉ is —O(C₁-C₂₄)alkyl.
 10. The compound of claim 1 wherein thecompound is:


11. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositioncomprising a compound of claim 10 and a pharmaceutically acceptablecarrier.
 13. The compound:

or a salt or solvate thereof.
 14. A pharmaceutical compositioncomprising a compound of claim 13 and a pharmaceutically acceptablecarrier.
 15. A method of treating an animal inflicted with a bacterialinfection comprising administering to an animal in need of suchtreatment an effective amount of a compound of claim
 1. 16. A method ofkilling or inhibiting a bacteria comprising contacting the bacteria withan effective amount of a compound of claim
 1. 17. The method of claim16, wherein the contacting is in vitro.
 18. The method of claim 16,wherein the contacting is in vivo.
 19. A pharmaceutical compositionsuitable for oral administration comprising a compound of claim 1effective against anti-vancomycin-resistant methicillin-resistantStaphylococcus aureus, and a pharmaceutical acceptable diluent orcarrier.